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US010226471B2 (12 ) United States Patent ( 10) Patent No. : US 10 ,226 ,471 B2 Shao et al . (45 ) Date of Patent: Mar. 12 , 2019 (54 ) MODIFIED -RELEASE DOSAGE FORMS OF (52 ) U . S . CI. 5 -HT , AGONISTS USEFUL FOR WEIGHT CPC ...... A61K 31 /55 (2013 .01 ) ; A23P 20 / 12 MANAGEMENT (2016 .08 ); A61K 9/ 0053 (2013 .01 ); (Continued ) ( 71 ) Applicant: Arena Pharmaceuticals, Inc. , San (58 ) Field of Classification Search Diego , CA (US ) CPC ...... A61K 31/ 55 ; A61K 9 /0053 ( 72 ) Inventors: Zezhi Jesse Shao , San Diego , CA (US ) ; See application file for complete search history. Anthony C . Blackburn , San Diego , CA (US ) ; Andrew J . Grottick , Chula (56 ) References Cited Vista, CA (US ) ; Michael E . Morgan , San Diego , CA (US ) ; Jaimie Karyn U . S . PATENT DOCUMENTS Rueter , San Diego , CA (US ) ; Anna 2 , 900 ,415 A 8 / 1959 Biel Shifrina , San Diego , CA (US ) ; Scott 3 , 652 , 543 A 3 / 1972 Hoegerle Stirn , San Diego , CA (US ) ; Libo Yang , (Continued ) San Diego , CA (US ) ; Woo Hyun Yoon , San Diego , CA (US ) FOREIGN PATENT DOCUMENTS (73 ) Assignee : Arena Pharmaceuticals , Inc . , San AU 515 236 3 / 1981 Diego , CA (US ) CA 1090797 12 / 1980 (Continued ) ( * ) Notice : Subject to any disclaimer , the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U . S . C . 154 (b ) by 0 days. Gohe , M . I et al. “ Advanced formulation design of venlafaxine (21 ) Appl. No. : 15 /429 , 221 hydrochloride coated and triple -layer tablets containing hypromel lose ” , 2009, Pharm Dev Technol, 14 :6 , 650 -658 . * (22 ) Filed : Feb . 10 , 2017 (Continued ) (65 ) Prior Publication Data Primary Examiner — Gina C Justice US 2017 /0246179 A1 Aug. 31, 2017 ( 74 ) Attorney , Agent, or Firm — Fish & Richardson P. C . Related U . S . Application Data ( 57 ) ABSTRACT (63 ) Continuation of application No. 13 /820 , 107, filed as The present invention relates to methods for weight man application No. PCT/ US2011 /049914 on Aug . 31 , agement that utilize modified -release dosage forms compris 2011 , now abandoned . ing ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - ben (Continued ) zazepine salts and crystalline forms thereof. The present invention further relates to ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 (51 ) Int. Ci. tetrahydro -1H -3 - benzazepine salts , crystalline forms thereof A61K 9 / 20 ( 2006 . 01) and modified - release dosage forms comprising them . A61K 9 / 28 (2006 .01 ) (Continued ) 7 Claims, 58 Drawing Sheets

PXRD of Compound 1 Hydrochloride Salt, Hemihydrate Form III

.2 :-

- 1 2 -.

*-+

1. 2222'* +

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17 US 10 , 226 , 471 B2 Page 2

Related U . S . Application Data 7 , 241, 805 B2 * 7 /2007 Oberegger ...... A61K 9 / 2027 424 / 464 (60 ) Provisional application No . 61/ 402 ,578 , filed on Sep . 7 ,514 ,422 B2 4 / 2009 Smith et al . 7 , 704 , 993 B2 4 / 2010 Smith et al . 1 , 2010 , provisional application No . 61 /403 , 143 , filed 7 ,977 , 329 B2 7 / 2011 Smith et al . on Sep . 10 , 2010 . 8 , 153 ,621 B2 4 / 2012 Behan et al. 8 , 168 ,614 B2 * 5 /2012 Baker ...... A61K 31/ 69 (51 ) Int. CI. 514 /64 A61K 31/ 55 ( 2006 . 01 ) 8 , 168 ,624 B2 5 /2012 Agarwal et al. A61K 45 / 06 ( 2006 .01 ) 8 , 168 ,782 B2 5 / 2012 Weigl et al. 8 , 207 , 158 B2 6 / 2012 Smith et al . A61K 9 / 00 ( 2006 .01 ) 8 , 273 ,734 B1 9 / 2012 Smith et al. C07D 223 / 16 ( 2006 . 01 ) 8 , 299 , 241 B2 10 / 2012 Gharbaoui et al . A61K 31 / 135 ( 2006 . 01 ) 8 , 367, 657 B2 2 / 2013 Wolgast A61K 31/ 155 ( 2006 .01 ) 8 , 501, 935 B2 8 / 2013 Weigl et al . A23P 20 / 12 8 ,546 , 379 B2 10 / 2013 Smith et al. ( 2016 .01 ) 8 ,575 , 149 B2 11/ 2013 Smith et al. ( 52 ) U . S . CI. 8 ,697 ,686 B2 * 4 /2014 Agarwal . .. . C07D 223 / 16 CPC ...... A61K 9 /2013 (2013 . 01 ) ; A61K 9 /2018 514 /217 . 01 ( 2013 .01 ); A61K 9 /2054 ( 2013 . 01 ); A61K 8 , 802 , 845 B2 8 / 2014 Weigl et al. 9 /2846 ( 2013 .01 ) ; A6IK 9 /2866 ( 2013 .01 ) ; 8 , 846 , 906 B2 9 /2014 Smith et al. A61K 31 / 135 ( 2013 . 01 ) ; A61K 31/ 155 8 ,946 ,207 B2 2/ 2015 Wolgast et al. 8 , 980 ,881 B2 * 3 / 2015 Agarwal ...... CO7D 223 / 16 (2013 .01 ) ; A61K 45 /06 ( 2013 .01 ) ; C07D 514 / 217 .01 223 / 16 (2013 .01 ) 8 , 993 , 750 B23 / 2015 Smith et al . 8, 999, 970 B2 * 4 /2015 Anderson ...... A61K 31/ 55 ( 56 ) References Cited 436 / 98 9 ,045 , 431 B2 * 6 /2015 Blackburn ...... A61K 31/ 55 U . S . PATENT DOCUMENTS 9 , 102 ,627 B28 / 2015 Wolgast et al. 9 , 169, 213 B2 * 10 / 2015 Sanchez ...... 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- ...- US 10 , 226 ,471 B2 MODIFIED - RELEASE DOSAGE FORMS OF There are problems however with the BMI definition in 5 -HT20 AGONISTS USEFUL FOR WEIGHT that it does not take into account the proportion of body mass MANAGEMENT that is muscle in relation to fat ( adipose tissue) . To account for this , obesity can also be defined on the basis of body fat This application is a 35 USC 371 National Stage Entry of 5 content: greater than 25 % in males and greater than 30 % in PCT /US2011 / 049914 filed Aug . 31 , 2011, and claims the females. benefit of U . S . Provisional Application No . 61 /403 , 143 , filed Obesity considerably increases the risk of developing cardiovascular diseases as well. Coronary insufficiency, Sep . 10 , 2010 , and 61/ 402 , 578 , filed Sep . 1 , 2010 , each of atheromatous disease , and cardiac insufficiency are at the which is incorporated by reference in its entirety for all 10 forefront of the cardiovascular complications induced by purposes . obesity . It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would FIELD OF THE INVENTION decrease by 25 % and the risk of cardiac insufficiency and of cerebral vascular accidents would decrease by 35 % . The The present invention relates to methods for weight 15 incidence of coronary diseases is doubled in subjects less management that utilize modified -release dosage forms than 50 years of age who are 30 % overweight. The diabetes comprising ( R ) - 8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 -tetrahydro - 1H -3 patient faces a 30 % reduced lifespan . After age 45, people benzazepine salts and crystalline forms thereof. The present with diabetes are about three times more likely than people invention further relates to ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 without diabetes to have significant heart disease and up to tetrahydro - 1H - 3 - benzazepine salts , crystalline formsthereof 20 five times more likely to have a stroke . These findings and modified - release dosage forms comprising them . emphasize the inter - relations between risks factors for dia betes and coronary heart disease and the potential value of BACKGROUND OF THE INVENTION an integrated approach to the prevention of these conditions based on the prevention of obesity ( Perry, I. J. , et al ., BMJ Obesity is a life -threatening disorder in which there is an 25 310 , 560 - 564 ( 1995 ) ) . increased risk of morbidity and mortality arising from Diabetes has also been implicated in the development of concomitant diseases such as type II diabetes, hypertension , kidney disease , eye diseases and nervous system problems. stroke , cancer and gallbladder disease . Kidney disease , also called nephropathy , occurs when the Obesity is now a major healthcare issue in the Western kidney ' s “ filter mechanism ” is damaged and protein leaks World and increasingly in some third world countries. The 30 into urine in excessive amounts and eventually the kidney increase in numbers of obese people is due largely to the fails . Diabetes is also a leading cause of damage to the retina increasing preference for high fat content foods but also the at the back of the eye and increases risk of cataracts and decrease in activity in most people ' s lives. Currently about glaucoma. Finally , diabetes is associated with nerve damage , 30 % of the population of the USA is now considered obese . especially in the legs and feet , which interferes with the Whether someone is classified as overweight or obese isS 35 ability to sense pain and contributes to serious infections . generally determined on the basis of their body mass index Taken together, diabetes complications are one of the (BMI ) which is calculated by dividing body weight (kg ) by nation ' s leading causes of death . height squared (m2 ) . Thus, the units of BMI are kg /m2 and The first line of treatment is to offer diet and life style it is possible to calculate the BMI range associated with advice to patients such as reducing the fat content of their minimum mortality in each decade of life . Overweight 18is 40 diet and increasing their physical activity . However, many defined as a BMI in the range 25 - 30 kg /m² , and obesity as patients find this difficult and need additional help from drug a BMI greater than 30 kg /m² ( see table below ). therapy to maintain results from these efforts . Most currently marketed products have been unsuccessful as treatments for obesity because of a lack of efficacy or Classification Of Weight By Body Mass Index (BMI ) 45 unacceptable side - effect profiles . The most successful drug BMI CLASSIFICATION so far was the indirectly acting 5 -hydroxytryptamine ( 5 -HT ) agonist d - fenfluramine (ReduxTM ) but reports of cardiac < 18 . 5 Underweight 18 . 5 - 24 . 9 Normal valve defects in up to one third of patients led to its 25 . 0 - 29 . 9 Overweight withdrawal by the FDA in 1998 . 30 . 0 - 34 . 9 Obesity (Class I ) 50 In addition , two drugs have been launched in the USA and 35 . 0 - 39 . 9 Obesity ( Class II ) Europe: Orlistat (XenicaTM ) , a drug that prevents absorption > 40 Extreme Obesity ( Class III ) of fat by the inhibition of pancreatic lipase , and Sibutramine (ReductilTM ), a 5 -HT / noradrenaline re -uptake inhibitor. As the BMI increases there is an increased risk of death However, side effects associated with these products may from a variety of causes that are independent of other risk 55 limit their long -term utility . Treatment with XenicaTM is factors . The most common diseases associated with obesity reported to induce gastrointestinal distress in some patients , are cardiovascular disease (particularly hypertension ), dia - while Sibutramine has been associated with raised blood betes (obesity aggravates the development of diabetes ) , gall pressure in some patients . bladder disease (particularly cancer ) and diseases of repro Serotonin ( 5 -HT ) neurotransmission plays an important duction . The strength of the link between obesity and 60 role in numerous physiological processes both in physical specific conditions varies . One of the strongest is the link and in psychiatric disorders . 5 -HT has been implicated in the with type 2 diabetes . Excess body fat underlies 64 % of cases regulation of feeding behavior . 5 -HT is believed to work by of diabetes in men and 77 % of cases in women (Seidell , inducing a feeling of satiety , such that a subject with Semin . Vasc . Med ., 5 : 3 - 14 ( 2005 ) ) . Research has shown that enhanced 5 -HT stops eating earlier and fewer calories are even a modest reduction in body weight can correspond to 65 consumed . It has been shown that a stimulatory action of a significant reduction in the risk of developing coronary 5 -HT on the 5 -HT2c receptor plays an important role in the heart disease . control of eating and in the anti -obesity effect of d - fenflu US 10 , 226 , 471 B2 ramine . As the 5 -HT2c receptor is expressed in high density applications 61/ 402 , 565 and 61 /403 , 185 ; each of which is in the brain ( notably in the limbic structures , extrapyramidal i ncorporated herein by reference in its entirety . pathways, thalamus and hypothalamus i . e . PVN and DMH , ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben and predominantly in the choroid plexus) and is expressed in zazepine hydrochloride (lorcaserin hydrochloride ) is an ago low density or is absent in peripheral tissues , a selective 5 nist of the 5 -HT2c receptor and shows effectiveness at 5 -HT2c receptor agonist can be a more effective and safe reducing obesity in animal models and humans. In Decem anti -obesity agent. Also , 5 -HT , knockout mice are over - ber 2009 , Arena Pharmaceuticals submitted a New Drug weight with cognitive impairment and susceptibility to sei Application , or NDA , for lorcaserin to the FDA . The NDA submission is based on an extensive data package from zure . ble in 10 lorcaserin ' s clinical development program that includes 18 It is believed that the 5 -HT2c receptor may play a role in clinical trials totaling 8 ,576 patients . The pivotal phase 3 obsessive compulsive disorder, some forms of depression , clinical trial program evaluated nearly 7 ,200 patients treated and epilepsy . Accordingly , agonists can have anti - panic for up to two years, and showed that lorcaserin consistently properties , and properties useful for the treatment of sexual produced significant weight loss with excellent tolerability . dysfunction . About two - thirds of patients achieved at least 5 % weight In sum , the 5 -HT2c receptor is a receptor target for the loss and over one -third achieved at least 10 % weight loss . treatment of obesity and psychiatric disorders , and it can be On average , patients lost 17 to 18 pounds or about 8 % of seen that there is a need for selective 5 -HT2c agonists which their weight. Secondary endpoints , including body compo safely decrease food intake and body weight. sition , lipids , cardiovascular risk factors and glycemic The salts and formulations of the present invention com - 20 parameters improved compared to placebo . In addition , prise the selective 5 -HT2c - receptor agonist ( R ) - 8 -chloro - 1 - heart rate and blood pressure went down. Lorcaserin did not methyl- 2 ,3 ,4 ,5 -tetrahydro -1H - 3- benzazepine (Compound increase the risk of cardiac valvulopathy. Lorcaserin 1 ) , and are useful for, inter alia , weight management, includ - improved quality of life , and there was no signal for depres ing weight loss and the maintenance of weight loss . Com - sion or suicidal ideation . The only adverse event that pound 1 is disclosed in PCT patent publication WO2003/ 25 exceeded the placebo rate by 5 % was generally mild or 086303 , which is incorporated herein by reference in its moderate , transientheadache . Based on a normal BMIof 25 , entirety . patients in the first phase 3 trial lost about one - third of their excess body weight. The average weight loss was 35 pounds or 16 % of body weight for the top quartile of patients in the 1 30 second phase 3 trial. An immediate - release film - coated 10 -mg tablet was developed for the phase 3 clinical trials and commercial launch of lorcaserin , but there remains a need for modified NH release formulations to provide a delay in , and/ or continuous 35 drug -release over an extended period of time. Modified release dosage forms elevate trough plasma levels and are suitable for use in once - a -day ( q . d .) dosing regimens. Fur Various synthetic routes to ( R )- 8 -chloro - 1 -methyl - 2 ,3 , 4, thermore , modified -release dosage forms reduce the drug 5 - tetrahydro - 1H - 3 -benzazepine , its related salts , enantiom plasma concentration peak : trough ratio and can thereby ers , crystalline forms, and intermediates, have been reported 40 decrease the incidence and severity of the adverse effects of in PCT publications , WO 2005 /019179 , WO 2006 /069363 , intermittent dosing . WO 2007 / 120517 , WO 2008 / 070111 , WO 2009/ 111004 , The choice of modified -release technology depends upon and in U . S . provisional application 61 / 396 ,752 each of the plasma concentration profile desired and the active which is incorporated herein by reference in its entirety . pharmaceutical ingredient (API ) solubility . The drug mol Combinations of ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetra - 45 ecule must have appropriate pharmacokinetics and sufficient hydro - 1H - 3 -benzazepine with other agents, including with solubility , permeability , and stability throughout the GI tract out limitation , phentermine , and uses of such combinations for a successful modified -release formulation . The salts and in therapy are described in WO 2006 / 071740 , which is formulations described herein help meet these and other incorporated herein by reference in its entirety . needs. The following United States provisional applications are 50 related to ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 SUMMARY OF THE INVENTION benzazepine : 61/ 402 , 578 ; 61/ 403 , 143 ; 61 / 402 ,580 ; 61/ 402 , 628 ; 61/ 403 , 149 ; 61/ 402 , 589 ; 61/ 402 , 611 ; 61 /402 , 565 ; One aspect of the present invention pertains to modified 61/ 403 , 185 ; each of which is incorporated herein by refer - release dosage forms comprising a therapeutically effective ence in its entirety . 55 amount of ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 The following applications are related to ( R ) - 8 - chloro - 1 - benzazepine or a pharmaceutically acceptable salt, solvate , methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine and have the or hydrate thereof. same filing date as the subject application : a PCT application One aspect of the present invention pertains to methods PCT/ US2011 /049935 which claims priority to U .S . provi- for weight management, comprising administering to an sional application 61/ 402 , 580 ; PCT application PCT/ 60 individual in need thereof, the modified - release dosage form US2011/ 049936 which claims priority to U . S . provisional of the present invention . applications 61/ 402 ,628 and 61/ 403 , 149 ; PCT application One aspect of the present invention pertains to a salt PCT/ US2011 /049953 which claims priority to U . S . provi selected from : ( R ) - 8 -chloro - 1 -methyl - 2 ,3 , 4 , 5 - tetrahydro sional application 61/ 402 , 589 ; PCT application PCT/ 1H - 3 - benzazepine hydroiodide salt ; ( R )- 8 - chloro - 1 -methyl US2011/ 049960 which claims priority to U . S . provisional 65 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine maleate salt ; ( R ) - 8 application 61/ 402 ,611 ; and PCT application PCT) chloro - 1 -methyl - 2, 3 ,4 , 5 -tetrahydro - 1H - 3 - benzazepine US2011049955 which claims priority to U . S . provisional fumarate salt ; and ( R ) - 8 - chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetra US 10 ,226 , 471 B2 hydro - 1H - 3 -benzazepine hemifumarate salt; ( R ) - 8 -chloro tions of the present invention , for use in a method of weight 1 -methyl - 2, 3 ,4 , 5 -tetrahydro - 1H - 3 -benzazepine orotate salt ; management in combination with a second anti -obesity ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben agent. zazepine di- acetamidobenzoate salt -cocrystal ; ( R ) - 8 -chloro One aspect of the present invention pertains to modified 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine trans - cinna - 5 release dosage forms, salts , and pharmaceutical composi mate salt ; (R )- 8 - chloro - 1- methyl - 2 ,3 , 4 , 5 - tetrahydro - 1H - 3 - tions of the present invention , for use in a method of weight benzazepine heminapadisilate salt ; ( R ) - 8 - chloro - 1 -methyl - management in combination with a second anti -obesity 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( + ) -mandelate salt; agent selected from : chlorphentermine , clortermine , phen and ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - ben - pentermine, and phentermine , and pharmaceutically accept zazepine hemipamoate salt; and pharmaceutically accept- 10 able salts, solvates , and hydrates thereof. able solvates and hydrates thereof. One aspect of the present invention pertains to modified One aspect of the present invention pertains to a pharma- release dosage forms, salts , and pharmaceutical composi ceutical composition comprising a salt of the present inven t ions of the present invention , for use in a method of weight tion , and a pharmaceutically acceptable carrier. management in combination with an anti -diabetes agent. One aspect of the present invention pertains to processes 15 One aspect of the present invention pertains to modified for preparing a pharmaceutical composition comprising release dosage forms, salts , and pharmaceutical composi admixing a salt of the present invention , and a pharmaceu - tions of the present invention , for use in a method of weight tically acceptable carrier. management in combination with metformin . One aspect of the present invention pertains to methods One aspect of the present invention pertains to methods of for weight management, comprising administering to an 20 manufacturing a pharmaceutical composition comprising : individual in need thereof , a therapeutically effective admixing a compound selected from : a salt of the present amount of a salt or a pharmaceutical composition of the invention and pharmaceutically acceptable solvates and present invention . hydrates thereof , with a pharmaceutically acceptable excipi One aspect of the present invention pertains to uses of ent . salts or pharmaceutical compositions of the present inven - 25 One aspect of the present invention pertains to methods of tion , in the manufacture of a medicament for weight man - manufacturing a modified -release dosage form comprising : agement in an individual. providing a compound selected from : (R )- 8 -chloro - 1 One aspect of the present invention pertains to salts , and methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine , and pharma pharmaceutical compositions of the present invention , for ceutically acceptable salts , solvates , and hydrates thereof; use in a method of treatment of the human or animal body 30 and formulating the compound into a modified - release dos by therapy . age form . One aspect of the present invention pertains to modified One aspect of the present invention pertains to methods release dosage forms, salts , and pharmaceutical composi- for weight management, comprising administering to an tions of the present invention , for use in a method of weight individual in need thereof, a modified -release dosage form management. 35 comprising a therapeutically effective dose of ( R ) - 8 - chloro One aspect of the present invention pertains to modified 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine or a phar release dosage forms, salts , and pharmaceutical composi maceutically acceptable salt , solvate or hydrate thereof. tions of the present invention , for use in a method of weight One aspect of the present invention pertains to modified management; wherein the weight management comprises release dosage forms comprising a therapeutically effective one or more of: weight loss , and maintenance ofweight loss . 40 dose of (R ) -8 -chloro - 1 -methyl - 2, 3 ,4 ,5 - tetrahydro - 1H -3 One aspect of the present invention pertains to modified - benzazepine or a pharmaceutically acceptable salt, solvate release dosage forms, salts , and pharmaceutical composi- or hydrate thereof. tions of the present invention , for use in a method of weight One aspect of the present invention pertains modified management; wherein the weight management comprises release dosage forms comprising a therapeutically effective one or more of: weight loss , maintenance of weight loss , 45 dose of a salt selected from : (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 decreased food consumption , increasing meal- related sati- tetrahydro - 1H - 3 -benzazepine and pharmaceutically accept ety , reducing pre -meal hunger, and reducing intra -meal food able salts , solvates, and hydrates thereof, for use in a method intake . of weight management in an individual . One aspect of the present invention pertains to modified One aspect of the present invention pertains to certain release dosage forms, salts , and pharmaceutical composi - 50 salts of ( R ) -8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 tions of the present invention , for use as an adjunct to diet benzazepine (Compound 1 ) and pharmaceutically accept and exercise for weight management. able solvates and hydrates thereof. One aspect of the present invention pertains to modified One aspect of the present invention pertains to certain release dosage forms, salts , and pharmaceutical composi - salts of ( R ) -8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro - 1H - 3 tions of the present invention , for use in a method of weight 55 benzazepine (Compound 1 ) . management; wherein the individual in need of weight One aspect of the present invention pertains to crystalline management is selected from : an obese patient with an forms of ( R ) -8 -chloro - 1- methyl - 2 ,3 , 4 , 5 - tetrahydro - 1H -3 initial body mass index 230 kg /m² ; an overweight patient benzazepine hydroiodide salt . with an initial body mass index 227 kg /m2 in the presence One aspect of the present invention pertains to crystalline of at least one weight related comorbid condition , and an 60 forms of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 overweight patient with an initial body mass index 227 benzazepine maleate salt . kg /m² in the presence of at least one weightrelated comorbid One aspect of the present invention pertains to crystalline condition ; wherein the weight related co -morbid condition is forms of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 selected from : hypertension , dyslipidemia , cardiovascular benzazepine fumarate salt . disease , glucose intolerance , and sleep apnea . 65 One aspect of the present invention pertains to crystalline One aspect of the present invention pertains to modified forms of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 release dosage forms, salts , and pharmaceutical composi benzazepine hemifumarate salt . US 10 ,226 ,471 B2 One aspect of the present invention pertains to crystalline FIG . 4 : DMS of Compound 1 Hydrochloride Salt , Hemi forms of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - hydrate Form III. benzazepine orotate salt. FIG . 5 : PXRD of Compound 1 Hydroiodide Salt, Form I. One aspect of the present invention pertains to crystalline FIG . 6 : DSC and TGA of Compound 1 Hydroiodide Salt , forms of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - 5 Form I . benzazepine orotate salt hydrate. FIG . 7: DMS of Compound 1 Hydroiodide Salt, Form I. One aspect of the present invention pertains to crystallinethe FIG . 8 : PXRD of Compound 1 Maleate Salt , Form I . forms of (R )- 8 -chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H - 3 FIG . 9: DSC and TGA of Compound 1 Maleate Salt, Form benzazepine di- 4 -acetamidobenzoate salt- cocrystal methyl" * 10 FIG . 10 : DMS of Compound 1 Maleate Salt , Form I . ethyl ketone solvate . FIG . 11 : PXRD of Compound 1 Fumarate Salt, Form I . One aspect of the present invention pertains to crystalline FIG . 12 : DSC and TGA of Compound 1 Fumarate Salt , forms of ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 Form I. benzazepine trans- cinnamate salt . FIG . 13 : DMS of Compound 1 Fumarate Salt , Form I . One aspect of the present invention pertains to crystalline 15 FIG . 14 : PXRD of Compound 1 Hemifumarate Salt . Form forms of ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - I. benzazepine heminapadisilate salt . FIG . 15 : DSC and TGA of Compound 1 Hemifumarate One aspect of the present invention pertains to crystalline Salt . Form I. forms of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro -1H - 3 - FIG . 16 : DMS of Compound 1 Hemifumarate Salt , Form benzazepine heminapadisilate salt solvate 1 . 20 I . One aspect of the present invention pertains to crystalline FIG . 17 : PXRD of Compound 1 Orotate Salt, Form I. forms of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - FIG . 18 : DSC and TGA of Compound 1 Orotate Salt , benzazepine heminapadisilate salt solvate 2 . Form I . One aspect of the present invention pertains to crystalline FIG . 19 : DMS of Compound 1 Orotate Salt , Form I . forms of (R )- 8 -chloro - 1 -methyl - 2 ,3 , 4, 5 - tetrahydro - 1H - 3 - 25 FIG . 20 : PXRD of Compound 1 Orotate Salt Hydrate , benzazepine ( )- mandelate salt hydrate . Form I. One aspect of the present invention pertains to crystalline FIG . 21 : DSC and TGA of Compound 1 Orotate Salt forms of (R )- 8 - chloro -1 -methyl - 2 , 3, 4, 5 - tetrahydro - 1H -3 - Hydrate , Form I . benzazepine hemipamoate salt hydrate . FIG . 22 : DMS of Compound 1 Orotate Salt Hydrate , One aspect of the present invention pertains to pharma - 30 Form I . ceutical compositions comprising a salt of the present inven - FIG . 23 : PXRD of Compound 1 Di- 4 - acetamidobenzoate tion . Salt - Cocrystal Methyl Ethyl Ketone Solvate , Form I . One aspect of the present invention pertains to processes FIG . 24 : DSC and TGA of Compound 1 Di - 4 - acetami for preparing pharmaceutical compositions comprising dobenzoate Salt - Cocrystal Methyl Ethyl Ketone Solvate , admixing a salt of the present invention , and a pharmaceu - 35 Form I. tically acceptable carrier. FIG . 25 : DMS of Compound 1 Di- 4 -acetamidobenzoate One aspect of the present invention pertains to bulk Salt- Cocrystal Methyl Ethyl Ketone Solvate , Form I. pharmaceutical compositions suitable for themanufacture of FIG . 26 : PXRD of Compound 1 trans - Cinnamate Salt, dosage forms for weight management, comprising a salt of Form I . the present invention , and a pharmaceutically acceptable 40 FIG . 27 : DSC and TGA of Compound 1 trans - Cinnamate carrier . Salt, Form I. One aspect of the present invention pertains to processes FIG . 28 : DMS of Compound 1 trans -Cinnamate Salt , for preparing a bulk pharmaceutical composition suitable for Form I . the manufacture of dosage forms for weight management, FIG . 29 : PXRD of Compound 1 Heminapadisilate Salt, comprising admixing a salt of the present invention , and a 45 Form I . pharmaceutically acceptable carrier. FIG . 30 : DSC and TGA of Compound 1 Heminapadisilate One aspect of the present invention pertains to methods Salt, Form I. for weight management, comprising administering to an FIG . 31 : DMS of Compound 1 Heminapadisilate Salt , individual in need thereof, a therapeutically effective Form I . amount of a salt , or a pharmaceutical composition of the 50 FIG . 32 : PXRD of Compound 1 Heminapadisilate Salt present invention . Solvate 1 , Form I . One aspect of the present invention pertains to the use of FIG . 33 : DSC and TGA of Compound 1 Heminapadisilate a salt of the present invention in the manufacture of a Salt Solvate 1 , Form I . medicament for weight management in an individual. FIG . 34 : PXRD of Compound 1 Heminapadisilate Salt One aspect of the present invention pertains to salts and 55 Solvate 2 , Form I . pharmaceutical compositions of the present invention , for FIG . 35 : DSC and TGA of Compound 1 Heminapadisilate use in a method of treatment of the human or animal body Salt Solvate 2 , Form I . by therapy . FIG . 36 : PXRD of Compound 1 ( + ) -Mandelate Salt Hydrate, Form I. BRIEF DESCRIPTION OF THE DRAWINGS 60 FIG . 37 : DSC and TGA of Compound 1 ( + )- Mandelate Salt Hydrate , Form I . FIG . 1 : PXRD of Compound 1 Hydrochloride Salt, Hemi- FIG . 38 : DMS of Compound 1 ( + ) -Mandelate Salt hydrate Form III. Hydrate , Form I. FIG . 2 : DSC of Compound 1 Hydrochloride Salt , Hemi- FIG . 39 : PXRD of Compound 1 Hemipamoate Salt hydrate Form III . 65 Hydrate , Form I . FIG . 3: TGA of Compound 1 Hydrochloride Salt , Hemi- FIG . 40 : DSC and TGA of Compound 1 Hemipamoate hydrate Form III. Salt Hydrate , Form I . US 10 , 226 ,471 B2 10 FIG . 41: DMS of Compound 1 Hemipamoate Salt The term “ agonist” refers to a moiety that interacts with Hydrate , Form I. and activates a receptor, such as the 5 -HT2c serotonin FIG . 42: Upper Limit of Release of Compound 1 Hydro receptor, and initiates a physiological or pharmacological chloride Salt Hemihydrate , Form III from Modified - release response characteristic of that receptor. Formulation . 5 The term “ AUC ” refers to the area under a plasma FIG . 43: Pharmacokinetics Simulation of 20 -mg Modi concentration versus time curve . fied - release Formulation and 10 -mg Immediate -release ( IR ) The term " AUCO - " refers to the area under a plasma Tablets of Compound 1 Hydrochloride Salt Hemihydrate , concentration versus time curve from the time of dosing to Form III . time t . FIG . 44 : Dissolution Profile of Compound 1 Hydrochlo The term “ AUCO- int" refers to the area under a plasma ride Salt Hemihydrate , Form III Tablets Coated with Sure concentration versus time curve from the time of dosing lease® /Opadry® (85 / 15 ) . extrapolated to infinity . FIG . 45 : Effect of the Surelease® /Opadry® Ratio on The term " AUCH ” refers to the area under a plasma Compound 1 Hydrochloride Salt Hemihydrate , Form III concentration versus time curve for a given dosing interval Release . The term “ AUCiastSZ ” refers to the area under the plasma FIG . 46 : Effect of HPMC K4M Level on Compound 1 concentration versus time curve from the time of dosing to Hydrochloride Salt Hemihydrate , Form III Release . the last sampling time. In some embodiments AUCiast refers FIG . 47 : Effect of Surelease® /Opadry® Coating Level on to the area under the plasma concentration versus time curve Compound 1 Hydrochloride Salt Hemihydrate , Form III 20 from the time of dosing to the last sampling time of a Release . particular compound during the interval between any two FIG . 48 : Effect of Compound 1 Hydrochloride Salt Hemi consecutive doses of a medicament comprising the com hydrate, Form III Loading . pound or a salt , solvate , or hydrate thereof, up to the last FIG . 49 : Day 26 Efficacy of Compound 1 after PO dosed sampling time. In some embodiments , the compound is at 24 mg/ kg /day or Osmotic Pump Infusion at 15 . 1 mg/ kg ) 25 Compound 1 . In some embodiments , the medicament is a Rate , 0 .63 mg/ kg / h ) in Fed Male SD Rats. modified -release dosage form . FIG . 50 : Mean Plasma Concentration of Compound 1 The term " Cmax ” refers to the maximum (peak ) plasma after PO dosed at 24 mg /kg / day or Osmotic Pump Infusion concentration of a particular compound during the interval at 15 . 1 mg/ kg /day ( Infusion Rate , 0 .63 mg/ kg / h ) in Fed between any two consecutive doses of a medicament com Male SD Rats . 30 prising the compound or a salt , solvate , or hydrate thereof. FIG . 51 : Mean AUCiast ofCompound 1 after PO dosed at In some embodiments , the compound is Compound 1 . In 24 mg/ kg / day or Osmotic Pump Infusion at 15 . 1 mg/ kg /day some embodiments , the medicament is a modified - release ( Infusion Rate, 0 .63 mg/ kg /h ) in Fed Male SD Rats . dosage form . FIG . 52 : Mean Chor of Compound 1 after PO dosed at 24 The term “ Cin ” refers to the minimum ( trough ) plasma mg/ kg /day or Osmotic Pump Infusion at 15 . 1 mg/ kg / day 35 concentration of a particular compound during the interval ( Infusion Rate , 0 .63 mg/ kg /h ) in Fed Male SD Rats . between any two consecutive doses of a medicament com FIG . 53 : Individual Compound 1 Exposure Values after prising the compound or a salt, solvate , or hydrate thereof. PO (24 mg/ kg /day ) or SC Osmotic Pump Infusion ( 15 . 1 In some embodiments , the compound is Compound 1 . In mg/ kg /day , Infusion Rate , 0 .63 mg/ kg / h ) in Fed Male SD some embodiments , the medicament is a modified -release Rats . 40 dosage form . FIG . 54 : Days 1 - 26 Efficacy of Compound 1 after PO The term " functional coating” refers to a film coating on dosed at 24 mg/ kg / day or Osmotic Pump Infusion at 15 . 1 a tablet that provides a mechanism to restrict water ingress mg/ kg / day (Infusion Rate , 0 .63 mg/ kg /h ) in Fed Male SD into the tablet and subsequent diffusion of the API . Rats . The term “ individual ” refers to both humans and non FIG . 55 : Dissolution Profiles of Compound 1 Hydrochlo - 45 human mammals . Non -human mammals include but are not ride Salt Hemi- hydrate , Form III 20 -mg Modified -release limited to rodents such as mice and rats , etc . rabbits , dogs , Formulations with Soluble Coating . cats , swine , cattle , sheep , horses , and non -human primates FIG . 56 : Dissolution Profiles of Compound 1 Hydrochlo - such as monkeys and apes, etc . ride Salt Hemi-hydrate , Form III 20 -mg Modified - release The term “ immediate -release dosage form ” refers to a Formulations with Functional Polymer Coating . 50 formulation which rapidly disintegrates upon oral adminis FIG . 57: Immediate -Release Mean Plasma Compound 1 tration to a human or other animal releasing an active Concentrations Versus Time on Day 1 in Humans . pharmaceutical ingredient ( API) from the formulation . FIG . 58 : Immediate -Release Mean Plasma Compound 1 Examples of immediate release dosage forms comprising Concentrations Versus Time on Day 14 in Humans . Compound 1 include , but are not limited to , the immediate 55 release formulation of Example 5 herein . In some embodi DETAILED DESCRIPTION ments the T80 % of the immediate - release dosage form is less than 3 hours . In some embodiments the T80 % of the It should be appreciated that certain features of the immediate - release dosage form is less than 1 hour. In some invention , which are , for clarity , described in the context of embodiments the T80 % of the immediate -release dosage separate embodiments , can also be provided in combination 60 form is less than 30 minutes . In some embodiments the in a single embodiment. Conversely , various features of the T80 % of the immediate - release dosage form is less than 10 invention which are , for brevity , described in the context of minutes. a single embodiment, can also be provided separately or in An “ immediate - release method for weightmanagement " any suitable subcombination . comprises administering to an individual in need thereof an Definitions 65 immediate -release dosage form . For clarity and consistency , the following definitions will The term “ modified - release dosage form ” refers to any be used throughout this patent document. formulation that, upon oral administration to a human or US 10 ,226 ,471 B2 11 12 other animal, releases an API at a slower rate over an The term " treatment” as used herein refers to one or more extended period of time when compared to an immediate of the following: release dosage - form of the API. For example, a modified ( 1 ) prevention of a disease , for example , prevention of a release tablet comprising Compound 1 administered orally disease , condition or disorder in an individual that may be to a human or other animal releases Compound 1 more 5 predisposed to the disease , condition or disorder but does not slowly and over a longer period of time than does an yet experience or display the pathology or symptomatology of the disease ; immediate - release tablet comprising Compound 1 adminis ( 2 ) inhibition of a disease , for example , inhibition of a tered orally to a human or other animal ; and a modified disease , condition or disorder in an individual that is expe release suspension comprising Compound 1 administered110 riencing or displaying the pathology or symptomatology of orally to a human or other animal releases Compound 1 " the disease , condition or disorder (i .e . , arresting further more slowly and over a longer period of time than an development of the pathology and / or symptomatology ) ; and immediate -release suspension comprising Compound 1 ( 3 ) amelioration of a disease , for example , amelioration of administered orally to a human or other animal. a disease , condition or disorder in an individual that is The term “ total plasma exposure ” refers to the totaltal dredarea 15 experiencing or displaying the pathology or symptomatol under a drug plasma concentration versus time curve over a ogy of the disease , condition or disorder ( i. e . , reversing the specified time period The term “ pharmaceutical composi pathology and /or symptomatology ). tion ” refers to a composition comprising at least one active Whether an individual is in need of treatment is a judg ingredient; including but not limited to Compound 1 and mentmade by a caregiver ( e . g . nurse practitioner, physician , pharmaceutically acceptable salts , solvates , and hydrates 20 physician assistant, nurse , etc. in the case of humans ; thereof, whereby the composition is amenable to investiga veterinarian in the case of animals , including non -human tion for a specified , efficacious outcome in a mammal ( for mammals ) that an individual or animal requires or will example , without limitation , a human ) . Those of ordinary benefit from treatment. This judgment is made based on a skill in the art will understand and appreciate the techniques variety of factors that are in the realm of a caregiver ' s appropriate for determining whether an active ingredient has 25 expertise , but that includes the knowledge that the individual a desired efficacious outcome based upon the needs of the or animal is ill , or will become ill , as the result of a disease , artisan . condition or disorder that is treatable by Compound 1 and The term " rate -controlling membrane ” refers to an inert pharmaceutically acceptable salts , solvates, and hydrates membrane barrier through which a drug diffuses at a con - thereof. Accordingly , Compound 1 and pharmaceutically trolled rate . 30 acceptable salts , solvates , and hydrates thereof can be used The term “ rate - controlling polymer ” refers to an excipient in a protective or preventive manner ; or Compound 1 and which upon administration as a component of a modified pharmaceutically acceptable salts , solvates , and hydrates release tablet, becomes hydrated and forms a gel layer on the thereof can be used to alleviate , inhibit or ameliorate a periphery of the tablet which modulates further water pen - disease , condition or disorder . etration and subsequent drug diffusion and release . 35 The term " weight management” as used herein refers to The term “ T80 % ” refers to the time needed to achieve controlling body weight and in the context of the present 80 % cumulative release of an API from a particular formu invention is directed toward weight loss and the mainte lation comprising the API. nance of weight loss (also called weight maintenance The term “ tmar ” refers to the time to maximum concen - herein ) . In addition to controlling body weight, weight tration of a particular compound during the interval between 40 management includes controlling parameters related to body any two consecutive doses of a medicament comprising the weight, for example , BMI, percent body fat and waist compound or a salt , solvate , or hydrate thereof. In some circumference . For example , weight management for an embodiments , the compound is Compound 1 . In some individual who is overweight or obese can mean losing embodiments , the medicament is a modified - release dosage weight with the goal of keeping weight in a healthier range . form . 45 Also , for example , weight management for an individual The term “ therapeutically effective amount” refers to the who is overweight or obese can include losing body fat or amount of active compound or pharmaceutical agent that circumference around the waist with or without the loss of elicits the biological or medicinal response in a tissue , body weight. system , animal, individual or human that is being sought by The term “ maintenance of weight loss” or “ weight main a researcher, veterinarian , medical doctor or other clinician 50 tenance " as used herein refers to preventing , reducing or or caregiver or by an individual, which includes one or more controlling weight gain after weight loss. It is well known of the following: that weight gain often occurs after weight loss . Weight loss ( 1 ) Preventing the disease , for example, preventing a can occur, for example, from dieting , exercising , illness , disease , condition or disorder in an individual that may be drug treatment, surgery or any combination of these meth predisposed to the disease , condition or disorder but does not 55 ods, but often an individual that has lost weight will regain yet experience or display the pathology or symptomatology some or all of the lost weight. Therefore , weight mainte of the disease ; nance in an individual who has lost weight can include ( 2 ) Inhibiting the disease, for example , inhibiting a dis - preventing weight gain after weight loss , reducing the ease , condition or disorder in an individual that is experi - amount of weigh gained after weight loss, controlling encing or displaying the pathology or symptomatology of 60 weight gain after weight loss or slowing the rate of weight the disease , condition or disorder ( i. e ., arresting further gain after weight loss . development of the pathology and /or symptomatology ); and In Vivo Pharmacokinetics and Efficacy ( 3 ) Ameliorating the disease, for example , ameliorating a The pharmacokinetic behavior and efficacy of modified disease , condition or disorder in an individual that is expe - release dosage forms, including but not limited to extended riencing or displaying the pathology or symptomatology of 65 release dosage forms, can be simulated by dosing via the disease , condition or disorder ( i. e. , reversing the pathol- minipump infusion ( e . g . to rats into either intraperitoneal or ogy and / or symptomatology ) . subcutaneous space ) Immediate release tablets can be simu US 10 , 226 , 471 B2 13 14 lated by dosing via oral gavage. Dose comparisons can be tions. Administration of Compound 1 after a high - fat break made based upon exposure or absolute dose . Studies can be fast resulted in a statistically significant delay to the time of run chronically or sub - chronically with an ultimate endpoint maximum plasma concentrations compared to administra of body weight change . tion in the fasted state . Cmax was reduced by approximately Where increased efficacy is observed with continuous 5 10 % in the fed compared to fasted state , but a lack of food steady -state exposure relative to intermittent exposure and effect was not proven . There was no food effect on overall absolute dose or AUC are matched , this indicates that exposure to Compound 1 . Compound 1 was generally well extended release formulations in humans are viable methods tolerated when dosed in the fasted state and after a high - fat with which to improve efficacy without increasing absolute breakfast . There were a higher number of adverse events dose . 10 when dosed in the fasted state , ( 18 compared to 6 ) including Furthermore , a reduced peak -to - trough variation in drug two moderate intensity (nausea and headache ) and one plasma concentration with continuous steady - state exposure severe ( vomiting ) intensity events occurring in a single relative to intermittent exposure indicates that extended subject. Modified - release dosage forms comprising Com release formulations in humans will decrease the incidence pound 1 will decrease the incidence and severity of adverse and severity of any adverse effects associated with intermit - 15 effects associated with intermittent treatment, by increasing tent treatment, by lowering the Cmor and maintaining the the while maintaining the AUC . AUC ( see Tompson et al. , Epilepsia 2008 ; 49 :410 -417 ) . It has been demonstrated that chronic twice - daily oral For drug therapy to be successful, there is an optimal drug administration of Compound 1 hydrochloride salt to rats concentration range that must be achieved . This is the maintained on a high fat diet produced dose - dependent therapeutic window . The consequences of being above the 20 reductions in food intake and body weight gain that were therapeutic concentration increases the probability of maintained during a 4 -week study ( Thomsen et al. , J . untoward side effects . If the drug plasma concentration is Pharmacol. Exp . Ther. , 2008 325 : 577 -587 , hereby incorpo below the therapeutic range , clinical efficacy is limited . rated by reference in its entirety ). After oral administration of drug , the plasma concentrations number of experiments were performed in male rise to a maximum concentration (Cmar , peak ) . Over time, 25 Sprague -Dawley rats in order to determine whether continu the plasma concentration declines to a minimum ( trough ) ous steady - state exposure of Compound 1 differentially concentration (Cmin , trough ). Therapeutically , it is desirable affects body weight gain compared to intermittent exposure . to reduce the drug peak - to - trough concentration differences Rats were administered Compound 1 either by once -daily to decrease adverse effects , while maintaining the therapeu - oral gavage or by constant infusion to simulate the effect of tic effects . This is accomplished by lowering the Cmor , while 30 administering a modified -release formulation of Compound keeping the plasma exposure (AUC ) stable (Rowland and 1 . The objective was to determine if reducing the drug Tozer , Clinical Pharmacokinetics : Concepts and Applica - plasma concentration peak - to -trough ratio via continuous tions 3d ed ., Williams and Wilkins. 1995 ; Privitera , Epilepsy infusion , while maintaining AUC , increases body weight Currents, Vol. 8 , No. 5 , 2008 pp . 113 - 117 ) . Modified -release reduction compared to intermittent exposure . Prior to initi dosage forms comprising Compound 1 will decrease the 35 ating the chronic experiment, preliminary pharmacokinetic incidence and severity of adverse effects associated with experiments were conducted to determine Compound 1 intermittent treatment by reducing the drug peak - to - trough plasma exposure at steady - state after once -daily oral admin concentration differences , while maintaining the AUC . istration for six days and after constant infusion for four Therapeutically , it is desirable to reduce Cmax and / or the days. The AUCtau Dav o following oral dosing and systemic rate at which drug concentration increases in order to 40 clearance derived from constant infusion were used to decrease adverse effects, while maintaining therapeutic calculate the subcutaneous osmotic minipump dose needed effects . For drugs that exhibit a brain to plasma exposure to achieve an AUCtau similar to AUCtau Davo following oral ratio of greater than 1 , a reduction in Cmor or a reduction in dosing. the rate of drug concentration increase in plasma, results in One aspect of the present invention pertains to methods a greater corresponding reduction in the brain . This greater 45 for weight management, comprising administering to an reduction is important for decreasing adverse effects linked individual in need thereof, a modified - release dosage form to brain drug - concentration , for example, headache . A clini- comprising a therapeutically effective dose of ( R ) - 8 -chloro cal trial was performed that measured plasma and lumbar 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine or a phar cerebrospinal fluid (CSF ) concentrations of Compound 1 in maceutically acceptable salt, solvate , or hydrate thereof. healthy obese volunteers who took 10 mg of Compound 1 50 One aspect of the present invention pertains to methods hydrochloride salt twice - daily for 6 . 5 days . Upon adminis - for weight management, comprising administering to an tration of the first dose on day 1 , the human brain - to -plasma individual in need thereof, the modified -release dosage form exposure ratio for Compound 1 was less than 1 . Steady state of the present invention . was achieved in each subject after dosing for approximately In some embodiments , the method comprises a plurality 4 to 6 days . At steady state , the human brain - to -plasma 55 of administrations of the modified -release dosage form , with exposure ratio for Compound 1 was 1 . 7 . Modified -release a frequency wherein the average interval between any two dosage forms comprising Compound 1 will decrease the sequential the administrations is : at least about 24 hours ; or incidence and severity of adverse effects associated with about 24 hours . intermittent treatment, by lowering the Cmax and /or the rate In some embodiments , the method comprises a plurality at which drug concentration increases in the plasma and in 60 of administrations of the modified -release dosage form , and the brain , while maintaining the AUC . the modified - release dosage form is administered once - a Therapeutically , it is desirable to increase tmar to decrease day. adverse effects , while maintaining therapeutic effects. A In some embodiments , the plurality of administrations is : clinical trial was performed to evaluate the safety and at least about 30 ; at least about 180 ; at least about 365 ; or at pharmacokinetic profile of a single oral dose of Compound 65 least about 730 . 1 ( 10 mg ) administered to healthy male and female subjects In some embodiments , the method is more efficacious aged 18 to 60 years ( inclusive ) under fed and fasted condi- than an immediate -release method for weight management; US 10 ,226 ,471 B2 15 16 wherein the immediate -release method for weight manage - In some embodiments , the modified - release dosage form ment comprises administering to an individual in need comprises a core tablet and a film coating ; wherein the core thereof, at the frequency, the plurality of administrations of tablet comprises : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro an immediate - release dosage form comprising the therapeu - 1H - 3 -benzazepine hydrochloride salt hemihydrate , Form tically effective amount of ( R ) - 8 -chloro - 1 -methyl - 2 , 3 ,4 , 5 - 5 III ; mannitol; (hydroxypropyl )methyl cellulose ; microcrys tetrahydro - 1H - 3 - benzazepine or a pharmaceutically accept- talline cellulose ; and magnesium sterate ; and the film coat able salt, solvate , or hydrate thereof . ing comprises a water- soluble film coating . In some embodiments , the method is more efficacious In some embodiments , the modified - release dosage form than an immediate - release method for weight management; comprises a core tablet and a film coating , wherein the wherein the immediate - release method for weight manage - 10 weight to weight ratio of the core tablet to the coating is ment comprises administering to an individual in need about 20 : 1 ; and wherein the core tablet comprises : about 7 % thereof, an immediate -release dosage form comprising ( R ) - ( R ) - 8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 -tetrahydro - 1H - 3 -ben 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine or zazepine hydrochloride salt hemihydrate , Form III ; about a pharmaceutically acceptable salt , solvate , or hydrate 22. 5 % mannitol; about 50 % (hydroxypropyl )methyl cellu thereof; and wherein the total plasma exposure of the 15 lose ; about 20 % microcrystalline cellulose ; and about 0 . 5 % individual to ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - magnesium sterate ; and the film coating comprises a water 3 -benzazepine over the course of the immediate -release soluble film coating. method is equal to or greater than the total plasma exposure In some embodiments , the modified - release dosage form of the individual to ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetra comprises a core tablet and a film coating ; wherein the core hydro - 1H - 3 -benzazepine over the course of the method . 20 tablet comprises : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro In some embodiments , the plasma concentration of the 1H - 3 -benzazepine hydrochloride salt hemihydrate , Form ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben III; mannitol; (hydroxypropyl ) methyl cellulose; microcrys zazepine in the individual has a Cmax of: less than about 60 talline cellulose; and magnesium sterate ; and the film coat ng/ mL ; less than about 40 ng /mL ; less than about 20 ng /mL ; ing comprises : ethyl cellulose ; and (hydroxypropyl )methyl or less than about 10 ng/ mL . 25 cellulose . In some embodiments , the Cmax divided by the therapeu - In some embodiments , the modified -release dosage form tically effective amount is equal to : less than about 1x10 - 5 comprises a core tablet and a film coating , wherein the mL - 1 ; less than about 5x10 - mL - 1 ; less than about 1x10 - 6 weight to weight ratio of the core tablet to the coating is mL - 1 ; or less than about 5x10 - 7 mL - 1 about 20 : 1 ; and wherein the core tablet comprises : about 7 % In some embodiments , the Cmor occurs : more than 30 30 ( R ) - 8 -chloro - 1 -methyl - 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 -ben minutes after the administering ; more than 1 hour after the Zazepine hydrochloride salt hemihydrate , Form III , about administering ; or more than 2 hours after the administering . 22 . 5 % mannitol; about 50 % (hydroxypropyl ) methyl cellu In some embodiments , the mor occurs : more than 3 hours lose ; about 20 % microcrystalline cellulose ; and about 0 . 5 % after the administering ; more than 6 hours after the admin magnesium sterate ; and the film coating comprises: about istering; or more than 12 hours after the administering . 35 85 % ethyl cellulose ; and about 15 % ( hydroxypropyl )methyl In some embodiments, the average peak to trough ratio of cellulose ; or about 75 % ethyl cellulose ; and about 25 % the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , ( hydroxypropyl )methyl cellulose . 4 ,5 - tetrahydro - 1H - 3 -benzazepine in the individual is : less In some embodiments , the modified - release dosage form than about 3 : 1 ; less than about 2 : 1 ; less than about 1 . 5 : 1 ; or has a T80 % of: at least 3 h ; at least 6 h ; at least 9 h ; or at less than about 1 . 1 : 1 . 40 least 12 h . In some embodiments , the modified - release dosage form In some embodiments , the modified -release dosage form comprises a salt selected from : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , comprises a salt selected from : a pharmaceutically accept 4 , 5 - tetrahydro - 1H - 3 -benzazepine hydrochloride and phar able salt of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 maceutically acceptable solvates and hydrates thereof. benzazepine and pharmaceutically acceptable solvates and In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - 45 hydrates thereof, and wherein the salt has an aqueous 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine hydrochloride salt solubility of: less than about 200 mg/ mL at about room hemihydrate . temperature ; less than about 100 mg/ mL at about room In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - temperature ; less than about 50 mg/ mL at about room 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine hydrochloride salt temperature ; less than about 25 mg/ mL at about room hemihydrate , Form III . 50 temperature ; less than about 10 mg/ mL at about room In some embodiments , the modified -release dosage form temperature; or less than about 5 mg/ mL at about room further comprises (hydroxypropyl ) methyl cellulose . temperature . In some embodiments , the modified -release dosage form In some embodiments , the modified - release dosage form further comprises one or more ingredients selected from : comprises a salt selected from : ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , microcrystalline cellulose , mannitol, and magnesium stear - 55 4 ,5 - tetrahydro - 1H - 3 - benzazepine hydroiodide salt ; ( R ) - 8 ate . chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine In some embodiments , the modified -release dosage form maleate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H further comprises a film coating . 3 -benzazepine fumarate salt ; and (R ) - 8 - chloro - 1 -methyl - 2 , In some embodiments , the film coating comprises a 3 , 4 ,5 -tetrahydro - 1H - 3 -benzazepine hemifumarate salt; (R ) water- soluble film coating. 60 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - benzazepine In some embodiments , the film coating comprises ethyl orotate salt ; ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H cellulose . 3 -benzazepine di- acetamidobenzoate salt - cocrystal; ( R ) - 8 In some embodiments , the film coating further comprises chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine (hydroxypropyl ) methyl cellulose . trans - cinnamate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra In some embodiments , the ratio of the ethyl cellulose to 65 hydro - 1H - 3 -benzazepine heminapadisilate salt ; ( R ) - 8 the (hydroxypropyl )methyl cellulose is : about 75 : 25 ; about chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine ( + ) 80 : 20 ; or about 85 : 15 . mandelate salt ; and (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 US 10 , 226 , 471 B2 17 18 tetrahydro - 1H - 3 -benzazepine hemipamoate salt ; and In any of the methods of the present invention , the Cmax pharmaceutically acceptable solvates and hydrates thereof. is an average over a plurality of treated individuals . In some embodiments , the method comprises a plurality In some embodiments , the Cmar divided by the therapeu of administrations of the modified -release dosage form , with tically effective amount is equal to less than about 1x10 - 5 a frequency wherein the average interval between any two 5 mL - 1 . sequential administrations is at least about 24 hours . In some embodiments , the Cmax divided by the therapeu In some embodiments , the method comprises a plurality tically effective amount is equal to less than about 5x10 - 6 of administrations of the modified -release dosage form , with mL - 1 . a frequency wherein the average interval between any two In some embodiments , the Cmax divided by the therapeu sequential administrations is about 24 hours. 10 tically effective amount is equal to less than about 1x10 In some embodiments , the plasma concentration of the mL - 1 . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the Cmax divided by the therapeu zazepine in the individual has a Car of less than about 60 tically effective amount is equal to less than about 5x10 - 7 ng /mL . mL - 1. In some embodiments , the plasma concentration of the In some embodiments , the Cmar divided by the therapeu ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben tically effective amount is equal to between about 1x10 - 5 zazepine in the individual has a Cmax of less than about 40 mL -1 and about 1x10 - 7 mL - 1 ng /mL . In some embodiments , the Cmax divided by the therapeu In some embodiments , the plasma concentration of the 20 tically effective amount is equal to between about 1x10 - 5 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben mL - 1 and about 5x10 - 7 mL - 1 . zazepine in the individual has a Cmar of less than about 20 In some embodiments , the Cmax divided by the therapeu ng /mL . tically effective amount is equal to between about 1x10 - 5 In some embodiments , the plasma concentration of the mL - 1 and about 1x10 - 6 mL -1 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben - 25 In some embodiments , the mor divided by the therapeu zazepine in the individual has a Cmax of less than about 10 tically effective amount is equal to between about 1x10 - ) ng /mL . mL - 1 and about 5x10 - 6 mL - 1 . In some embodiments, the plasma concentration of the In some embodiments, the C . divided by the therapeu ( R ) -8 - chloro - 1 -methyl - 2 ,3 , 4 ,5 -tetrahydro - 1H -3 -ben zazepine in the individual has a Cmax of about 60 ng /mL to 30 mitically effective amount is equal to between about 5x10 - 6 about 5 ng/ mL . nl to 30 mL - 1 and about 1x10 - 7 mL - 1 . In some embodiments , the plasma concentration of the In some embodiments , the Cmax divided by the therapeu ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben tically effective amount is equal to between about 5x10 - 6 zazepine in the individual has a Cmax of about 60 ng/ mL to mL - 1 and about 5x10 - 7 mL - 1 . about 10 ng /mL . 35 In some embodiments , the Cmax divided by the therapeu In some embodiments , the plasma concentration of the tically effective amount is equal to between about 5x10° ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben mL - 1 and about 1x10 - mL - 1 . zazepine in the individual has a C of about 60 ng /mL to In some embodiments , the Cmax divided by the therapeu about 20 ng /mL . tically effective amount is equal to between about 1x10 - 6 In some embodiments , the plasma concentration of the 40 mL - - and about 1x10 ' ' mL - '. ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the Cmax divided by the therapeu zazepine in the individual has a Cmor of about 60 ng /mL to tically effective amount is equal to between about 1x10 - 6 about 40 ng/ mL . mL - 1 and about 5x10 - ? mL - 1. In some embodiments , the plasma concentration of the In some embodiments , the Cmax divided by the therapeu ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben - 45 tically effective amount is equal to between about 5x10 - 7 zazepine in the individual has a Cmax of about 40 ng /mL to mL - 1 and about 1x10 - 7 mL - 1 . about 5 ng /mL . In some embodiments , the plasma concentration of the In some embodiments , the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - ben ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben zazepine in the individual has a AUCiast of at least about zazepine in the individual has a Cmax of about 40 ng /mL to 50 1x10 - 3 h : 11g /mL . about 10 ng /mL . In some embodiments , the plasma concentration of the In some embodiments , the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben (R ) -8 - chloro - 1- methyl - 2 , 3 ,4 ,5 - tetrahydro - 1H -3 -ben zazepine in the individual has a Cmat of about 40 ng/ mL to zazepine in the individual has a AUCs of at least about about 20 ng/ mL . 55 1x10 - 2 h .ug / mL . In some embodiments , the plasma concentration of the In some embodiments , the plasma concentration of the ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben (R )- 8 -chloro - 1 -methyl - 2, 3 ,4 , 5 -tetrahydro - 1H - 3 -ben zazepine in the individual has a Cmax of about 20 ng/ mL toto zazepine in the individualhas a AUCjast of at least about 0 . 1 about 5 ng /mL . h .ug / mL . In some embodiments , the plasma concentration of the 60 In some embodiments , the plasma concentration of the ( R ) -8 - chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H -3 -ben ( R ) - 8 -chloro - 1 -methyl - 2, 3 ,4 ,5 - tetrahydro - 1H - 3 -ben zazepine in the individual has a maxmor of about 20 ng /mL to zazepine in the individual has a AUCo of at least about 1 about 10 ng /mL . h ug/ mL . In some embodiments , the plasma concentration of the In some embodiments , the plasma concentration of the ( R )- 8 - chloro - 1 -methyl - 2 , 3 ,4 ,5 - tetrahydro - 1H - 3 -ben 65 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben zazepine in the individual has a Cmax of about 10 ng /mL to zazepine in the individual has a AUCiast of at least about 10 about 5 ng/ mL . h ‘ug / mL . US 10 , 226 ,471 B2 19 20 In some embodiments , the plasma concentration of the In some embodiments , the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben zazepine in the individual has a AUCjast of at least about 100 zazepine in the individual has a AUCiast of between about 1 h•ug/ mL . hug /mL and about 200 h .ug /mL . In any of the methods of the present invention , the 5 In some embodiments , the plasma concentration of the AUC is an average over a plurality of treated individuals . (R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 ,5 -tetrahydro - 1H - 3 -ben In some embodiments , the plasma concentration of the Zazepine in the individual has a AUCjast of between about 1 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben hug /mL and about 100 h .ug /mL . zazepine in the individual has a AUCiast of between about In some embodiments , the plasma concentration of the 1x10 - h -ug / mL and about 200 h ug /mL . 10 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the plasma concentration of the zazepine in the individual has a AUC , of between about 1 ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben hug /mL and about 10 hug /mL . zazepine in the individual has a AUCost of between about In some embodiments , the plasma concentration of the 1x10 - hug /mL and about 100 h -ug /mL . 15 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben In some embodiments , the plasma concentration of the zazepine in the individual has a AUCiast of between about 10 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben h•ug/ mL and about 200 h ug/ mL . zazepine in the individual has a AUCiast of between about In some embodiments , the plasma concentration of the 1x10 - h -ug / mL and about 10 h .ug / mL . ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the plasma concentration of the 20 zazepine in the individual has a AUCjast of between about 10 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben hug /mL and about 100 h .ug /mL . zazepine in the individual has a AUC of between about In some embodiments, the plasma concentration of the 1x10 - 3 h .ug / mL and about 1 h ug /mL . (R ) -8 -chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H - 3 -ben In some embodiments , the plasma concentration of the zazepine in the individual has a AUCost of between about ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben 25 100 h ug /mL and about 200 h ug /mL . zazepine in the individual has a AUCiast of between about In some embodiments , the AUCiast divided by the thera 1x10 - 3 hóug /mL and about 0 . 1 h .ug /mL . peutically effective amount is equal to at least about 1x10 - 6 In some embodiments , the plasma concentration of the h /mL . ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the AUCos divided by the thera zazepine in the individual has a AUCjast of between about 30 peutically effective amount is equal to at least about 1x10 - 5 1x10 - h -ug / mL and about 1x10 - 2 h .ug / mL . h /mL . In some embodiments , the plasma concentration of the In some embodiments, the AUC ; divided by the thera ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben peutically effective amount is equal to at least about 1x104 zazepine in the individual has a AUCost of between about h /mL . 1x10 - 2 h ug /mL and about 200 h ug /mL . 35 In some embodiments , the AUC , divided by the thera In some embodiments , the plasma concentration of the peutically effective amount is equal to at least about 1x10 - 3 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben h /mL . zazepine in the individual has a AUCiast of between about In some embodiments , the AUCjast divided by the thera 1x10 - 2 h ug/ mL and about 100 h .ug /mL . peutically effective amount is equal to at least about 1x10 - 2 In some embodiments , the plasma concentration of the 40 h /mL . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the AUCiast divided by the thera zazepine in the individual has a AUC of between about peutically effective amount is equal to between about 1x10 - 6 1x10 - 2 h .ug /mL and about 10 h .ug /mL . h /mL and about 0 . 1 h /mL . In some embodiments , the plasma concentration of the In some embodiments , the AUCiast divided by the thera ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben - 45 peutically effective amount is equal to between about 1x10 - 6 zazepine in the individual has a AUCiast of between about h /mL and about 1x10 - 2 h /mL . 1x10 - 2 h ug /mL and about 1 h ug/ mL . In some embodiments , the AUCtos divided by the thera In some embodiments , the plasma concentration of the peutically effective amount is equal to between about 1x10 - 6 ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben h /mL and about 1x10 - 3 h /mL . zazepine in the individual has a AUCiast of between about 50 In some embodiments , the AUClast divided by the thera 1x10 - 2 hug /mL and about 0 . 1 h .ug / mL . peutically effective amount is equal to between about 1x10 - 6 In some embodiments , the plasma concentration of the h /mL and about 1x104 h /mL . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the AUCiast divided by the thera zazepine in the individual has a AUCiast of between about peutically effective amount is equal to between about 1x10 - 6 0 . 1 h ug /mL and about 200 h -ug / mL . 55 h /mL and about 1x10 - h /mL . In some embodiments , the plasma concentration of the In some embodiments , the AUCjast divided by the thera ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben peutically effective amount is equal to between about 1x10 - 5 zazepine in the individual has a AUCiast of between about h /mL and about 0 . 1 h /mL . 0 . 1 h .ug /mL and about 100 h .ug /mL . In some embodiments, the AUCiast divided by the thera In some embodiments , the plasma concentration of the 60 peutically effective amount is equal to between about 1x10 - 5 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben h /mL and about 1x10 - 2 h /mL . zazepine in the individual has a AUCjast of between about In some embodiments , the AUCiast divided by the thera 0 . 1 h .ug /mL and about 10 h .ug / mL . peutically effective amount is equal to between about 1x10 - 5 In some embodiments , the plasma concentration of the h /mL and about 1x10 - 3 h /mL . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben - 65 In some embodiments , the AUCjast divided by the thera zazepine in the individual has a AUCast of between about peutically effective amount is equal to between about 1x10 - 5 0 .1 h ug /mL and about 1 h .ug /mL . h /mL and about 1x104 h /mL . US 10 ,226 ,471 B2 21 22 In some embodiments , the AUCtast divided by the thera In some embodiments , the average peak to trough ratio of peutically effective amount is equal to between about 1x104 the plasma concentration of the ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , h /mL and about 0 . 1 h / mL . 4 , 5 - tetrahydro - 1H - 3 - benzazepine in the individual is less In some embodiments , the AUCiast divided by the thera - than about 1 . 5 : 1 . peutically effective amount is equal to between about 1x1045 In some embodiments , the average peak to trough ratio of h /mL and about 1x10 - 2 h /mL . the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , In some embodiments , the AUCast divided by the thera 4 ,5 -tetrahydro - 1H - 3 - benzazepine in the individual is less peutically effective amount is equal to between about 1x104 than about 1 . 1 : 1 . h /mL and about 1x10 - h /mL . In any of the methods of the present invention , the peak In some embodiments , the AUCiast divided by the thera - 10 to trough ratio of the plasma concentration of the ( R ) - 8 peutically effective amount is equal to between about 1x10 % chloro - 1 -methyl - 2 ,3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine is an h /mL and about 0 . 1 h /mL . average over a plurality of treated individuals . In some embodiments , the AUCiast divided by the thera In some embodiments, the Cmor occurs more than 30 peutically effective amount is equal to between about 1x10 - 3 minutes after the administering . h /mL and about 1x10 - 2 h /mL . 15 In some embodiments , the Cmor occurs more than 1 hour In some embodiments , the AUCtast divided by the thera - after the administering. peutically effective amount is equal to between about 1x10 - 2 In some embodiments , the mor occurs more than 2 hours h /mL and about 0 . 1 h /mL . dioafter the administering . In some embodiments , the AUCjast divided by the Cmax is In some embodiments , the Cmax occurs more than 3 hours equal to at least about 5 h . 20 after the administering . In some embodiments , the AUCtast divided by the Cmax is In some embodiments , the Cmax occurs more than 6 hours equal to at least about 10 h . after the administering . In some embodiments, the AUC as divided by the Cmoris71AX In some embodiments , the Cmax occurs more than 12 equal to at least about 15 h . hours after the administering . In some embodiments , the AUCjast divided by the Cmax is 25 In some embodiments , the Cmax occurs more than 30 equal to at least about 25 h . minutes but less than 1 hour after the administering . In some embodiments , the AUCiast divided by the Cmax is In some embodiments , the Cmax occurs more than 30 equal to between about 5 h and about 50 h . minutes but less than 2 hours after the administering . In some embodiments , the AUC - divided by theC is In some embodiments , the Cor occurs more than 30 equal to between about 5 h and about 25 h . 30 minutes but less than 3 hours after the administering . In some embodiments, the AUCtos divided by the Cmax is In some embodiments , the Cmax occurs more than 30 equal to between about 5 h and about 15 h . minutes but less than 6 hours after the administering . In some embodiments, the AUC divided by the Cmis In some embodiments , the Cmor occurs more than 30 equal to between about 5 h and about 10 h . minutes but less than 12 hours after the administering . In some embodiments , the AUC divided by the Cmor is 35 In some embodiments , the mor occurs more than 1 hour equal to between about 10 h and about 50 h . but less than 2 hours after the administering . In some embodiments , the AUCtos divided by the Cmoris In some embodiments , the mor occurs more than 1 hour equal to between about 10 h and about 25 h . but less than 3 hours after the administering . In some embodiments, the AUC es divided by the Cmax is In some embodiments , the Cmor occurs more than 1 hour equal to between about 10 h and about 15 h . 40 but less than 6 hours after the administering . In some embodiments , the AUCjast divided by the Cmar is In some embodiments , the Cmat occurs more than 1 hour equal to between about 15 h and about 50 h . but less than 12 hours after the administering . In some embodiments , the AUCjast divided by the Cmar is In some embodiments , the Cmat occurs more than 2 hours equal to between about 15 h and about 25 h . but less than 3 hours after the administering . In some embodiments, the AUCtos divided by the Cmoris 45 In some embodiments , the mor occurs more than 2 hours equal to between about 25 h and about 50 h . but less than 6 hours after the administering . In some embodiments , the administering results in a Cmin In some embodiments , the Cmax occurs more than 2 hours of at least about 5 ng /mL and a Cmax of less than about 60 . but less than 12 hours after the administering . In some embodiments , the administering results in a C In some embodiments, the mor occurs more than 3 hours of at least about 5 ng /mL and a Cmor of less than about 40 50 but less than 6 hours after the administering. ng /mL . In some embodiments , the mor occurs more than 3 hours In some embodiments , the administering results in a Cmin but less than 12 hours after the administering. of at least about 5 ng /mL and a Cmor of less than about 20 In some embodiments , the Cmat occurs more than 6 hours ng /mL . but less than 12 hours after the administering . In some embodiments , the administering results in a min??? 55 In any of the methods of the present invention , the Cmormax of at least about 5 ng/ mL and a Cmax of less than about 10 is an average over a plurality of treated individuals . ng /mL . In some embodiments , the plurality of administrations is In some embodiments Cmin and Cmax are averages over a at least about 30 . plurality of treated individuals . In some embodiments , the plurality of administrations is In some embodiments, the average peak to trough ratio of 60 at least about 180 . the plasma concentration of the ( R ) -8 - chloro -1 -methyl - 2 , 3 , In some embodiments , the plurality of administrations is 4 , 5 -tetrahydro - 1H - 3 -benzazepine in the individual is less at least about 365 . than about 3 : 1 . In some embodiments , the plurality of administrations is In some embodiments, the average peak to trough ratio of at least about 730 . the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 65 In some embodiments , the method is more efficacious 4 ,5 -tetrahydro - 1H - 3 -benzazepine in the individual is less than an immediate -release method for weight management; than about 2 : 1 . wherein the immediate - release method for weight manage US 10 ,226 ,471 B2 23 24 ment comprises administering to an individual in need In some embodiments , the individual in need of weight thereof, at the frequency , the plurality of administrations of managementhas an initial body mass index 225 kg /m² in the an immediate -release dosage form comprising the therapeu presence of at least one weight related comorbid condition tically effective dose of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 ,5 - tet selected from : hypertension , dyslipidemia , cardiovascular rahydro - 1H - 3 -benzazepine or a pharmaceutically acceptable 5 disease , glucose intolerance , and sleep apnea . salt, solvate , or hydrate thereof. In some embodiments , the method for weight manage In some embodiments , the method is more efficacious ment further comprises administering phentermine to the individual. than an immediate - release method for weight management; One aspect of the present invention pertains to methods wherein the immediate - release method for weight manage 10 for the treatment of a disorder related to 5 -HT2c receptor ment comprises administering to an individual in need activity in an individual, comprising administering to an thereof, an immediate -release dosage form comprising ( R ) individual in need thereof, a modified - release dosage form 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine or of the present invention . a pharmaceutically acceptable salt , solvate , or hydrate One aspect of the present invention pertains to methods thereof; and wherein the AUCiast of ( R ) - 8 - chloro - 1 -methyl - 15 for the treatment of obesity , comprising administering to an 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine in the immediate -re individual in need thereof, a modified -release dosage form lease method is equal to or greater than the AUClast of of the present invention ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the method for the treatment of zazepine in the method . obesity further comprises the administration or prescription In some embodiments , the weightmanagement comprises 20 of phentermine . weight loss . In some embodiments , the method for the treatment of In some embodiments , the weight management further obesity further comprises gastric electrical stimulation . comprises maintenance of weight loss . One aspect of the present invention pertains to methods In some embodiments , the weight management comprises for inducing weight loss , BMIloss , waist circumference loss decreased food consumption . 25 or body fat percentage loss , comprising administering to an In some embodiments , the weightmanagement comprises individual in need thereof, a modified -release dosage form increasing meal- related satiety . of the present invention . In some embodiments , the weight management comprises One aspect of the present invention pertains to methods reducing pre -meal hunger . for inducing weight loss , BMI loss , waist circumference loss In some embodiments , the weightmanagement comprises 30 or body fat percentage loss in an individual in preparation of reducing intra -meal food intake . the individual for bariatric surgery , comprising administer In some embodiments , the weight management further ing to an individual in need thereof, a modified -release comprises a reduced -calorie diet. dosage form of the present invention . In some embodiments , the weight management further One aspect of the present invention pertains to methods comprises a program of regular exercise . 35 for maintaining weight loss , BMI loss, waist circumference In some embodiments , the weight management further loss or body fat percentage loss in an individual, comprising comprises both a reduced - calorie diet and a program of administering to an individual in need thereof, a modified regular exercise . release dosage form of the present invention . In some embodiments , the individual in need of weight One aspect of the present invention pertains to methods management is an obese patient with an initial body mass 40 for maintaining weight loss , BMI loss , waist circumference index > 30 kg /m2 . loss or body fat percentage loss in an individual following In some embodiments , the individual in need of weight bariatric surgery , comprising administering to an individual management is an overweight patient with an initial body in need thereof, a modified - release dosage form of the mass index 227 kg /m² in the presence of at least one weight present invention . related comorbid condition . 45 One aspect of the present invention pertains to methods In some embodiments, the weight related co - morbid for inducing satiety in an individual, comprising adminis condition is selected from : hypertension , dyslipidemia , car - tering to an individual in need thereof, a modified - release diovascular disease, glucose intolerance , and sleep apnea . dosage form of the present invention . In some embodiments , the method further comprises One aspect of the present invention pertains to methods administering phentermine to the individual . 50 for decreasing food intake in an individual, comprising In some embodiments , the individual in need of weight administering to an individual in need thereof , a modified management has an initial body mass index > 30 kg /m2 . release dosage form of the present invention . In some embodiments , the individual in need of weight One aspect of the present invention pertains to methods management has an initial body mass index 227 kg/ m² . for decreasing hunger in an individual, comprising admin In some embodiments , the individual in need of weight 55 istering to an individual in need thereof, a modified -release managementhas an initial body mass index 227 kg /m² in the presence of at least one weight related comorbid condition . One aspect of the present invention pertains to methods In some embodiments, the individual in need of weight for decreasing food cravings in an individual, comprising management has an initial body mass index 227 kg /m² in the administering to an individual in need thereof, a modified presence of at least one weight related comorbid condition 60 release dosage form of the present invention . selected from : hypertension , dyslipidemia , cardiovascular One aspect of the present invention pertains to methods disease , glucose intolerance , and sleep apnea . for increasing intermeal interval in an individual, compris In some embodiments , the individual in need of weight ing administering to an individual in need thereof, a modi management has an initial body mass index > 25 kg /m² . fied -release dosage form of the present invention . In some embodiments , the individual in need of weight 65 One aspect of the present invention pertains to methods managementhas an initial body mass index 225 kg / m in the for the treatment of a disorder selected from : schizophrenia , presence of at least one weight related comorbid condition . anxiety , depression , psychoses , and alcohol addiction , com US 10 ,226 ,471 B2 25 26 prising administering to an individual in need thereof, a In some embodiments , the modified - release dosage form modified -release dosage form of the present invention . comprises a core tablet and a coating ; wherein the core tablet In some embodiments , the disorder is schizophrenia . comprises: (R )- 8 -chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H - 3 In some embodiments , the disorder is anxiety . benzazepine hydrochloride salt hemihydrate , Form III ; man In some embodiments , the disorder is depression . 5 nitol; (hydroxypropyl ) methyl cellulose ; microcrystalline In some embodiments , the disorder is psychoses . cellulose ; and magnesium sterate ; and the coating com In some embodiments , the disorder is alcohol addiction . prises : ethyl cellulose ; and (hydroxypropyl ) methyl cellu In some embodiments , the modified -release dosage form lose . comprises (R )- 8 -chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H - 3 In some embodiments , the modified - release dosage form benzazepine hydrochloride ora pharmaceutically acceptable 10 comprises a core tablet and a coating, wherein the weight to weight ratio of the core tablet to the coating is about 20 : 1 ; solvate or hydrate thereof . and wherein the core tablet comprises : about 7 % ( R ) - 8 In some embodiments , the modified -release dosage form chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine comprises (R )- 8 - chloro - 1- methyl - 2 ,3 , 4 ,5 - tetrahydro -1H - 3 hydrochloride salt hemihydrate , Form III ; about 22 .5 % benzazepine hydrochloride salt hemihydrate . 15 mannitol; about 50 % (hydroxypropyl ) methyl cellulose ; In some embodiments , the modified - release dosage form about 20 % microcrystalline cellulose ; and about 0 . 5 % mag comprises ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 nesium sterate ; and the coating comprises : about 85 % ethyl benzazepine hydrochloride salt hemihydrate , Form III . cellulose ; and about 15 % (hydroxypropyl ) methyl cellulose . In some embodiments , the modified - release dosage form In some embodiments , the modified -release dosage form further comprises an excipient selected from : (hydroxypro - 20 comprises a core tablet and a coating , wherein the weight to pyl) methyl cellulose, Kollidon® SR , sodium carboxymethyl weight ratio of the core tablet to the coating is about 20 : 1 ; cellulose , Carbopol® , wax , and xanthan gum . and wherein the core tablet comprises : about 7 % ( R ) - 8 In some embodiments , the modified -release dosage form chloro - 1 -methyl - 2, 3 ,4 , 5 - tetrahydro - 1H - 3 -benzazepine further comprises (hydroxypropyl )methyl cellulose . hydrochloride salt hemihydrate , Form III ; about 22 . 5 % In some embodiments , the (hydroxypropyl ) methyl cellu - 25 mannitol; about 50 % (hydroxypropyl ) methyl cellulose ; lose comprises Methocel® K4M . about 20 % microcrystalline cellulose ; and about 0 . 5 % mag In some embodiments , the modified - release dosage form nesium sterate ; and the coating comprises : about 75 % ethyl further comprises one or more ingredients selected from : cellulose ; and about 25 % (hydroxypropyl ) methyl cellulose . microcrystalline cellulose , mannitol, and magnesium stear In some embodiments , the modified -release dosage form ate . 30 has a T80 % of at least 3 h . In some embodiments , the modified -release dosage form In some embodiments , the modified - release dosage form further comprises a film coating. has a T80 % of at least 6 h . In some embodiments , the film coating comprises In some embodiments , the modified - release dosage form Opadry® II Blue . has a T80 % of at least 9 h . In some embodiments , the film coating comprises ethyl 35 In some embodiments , the modified -release dosage form cellulose , Kollicoat® SR30D , Eudragit® , or cellulose has a T80 % of at least 12 h . acetate . In some embodiments , the modified - release dosage form In some embodiments , the film coating comprises ethyl comprises a salt selected from : a pharmaceutically accept cellulose . able salt of ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 In some embodiments , the ethyl cellulose comprises 40 benzazepine and pharmaceutically acceptable solvates and Surelease® . hydrates thereof, wherein the salt has an aqueous solubility In some embodiments , the film coating further comprises of less than about 200 mg/mL at about room temperature . (hydroxypropyl ) methyl cellulose . In some embodiments, the salt has an aqueous solubility In some embodiments , the (hydroxypropyl ) methyl cellu - of less than about 100 mg/ mL at about room temperature . lose comprises Opadry® . 45 In some embodiments , the salt has an aqueous solubility In some embodiments , the ethyl cellulose to the (hydroxy - of less than about 50 mg/ mL at about room temperature . propyl) methyl cellulose is about 75 : 25 . In some embodiments , the salt has an aqueous solubility In some embodiments , the ethyl cellulose to the (hydroxy - of less than about 25 mg/ mL at about room temperature . propyl) methyl cellulose is about 80 : 20 . In some embodiments, the salt has an aqueous solubility In some embodiments , the ethyl cellulose to the (hydroxy - 50 of less than about 10 mg/ mL at about room temperature . propyl) methyl cellulose is about 85 : 15 . In some embodiments , the salt has an aqueous solubility In some embodiments, the modified - release dosage form of less than about 5 mg/mL at about room temperature . comprises a core tablet and a coating ; wherein the core tablet I n some embodiments , the salt has an aqueous solubility comprises : ( R ) - 8 -chloro - 1 -methyl - 2 ,3 , 4 , 5 - tetrahydro - 1H - 3 - of less than about 200 mg/mL but more than about 0 .0001 benzazepine hydrochloride salt hemihydrate , Form III ;man - 55 mg/ mL at about room temperature . nitol; ( hydroxypropyl) methyl cellulose ; microcrystalline In some embodiments, the salt has an aqueous solubility cellulose; and magnesium sterate ; and the coating comprises of less than about 100 mg/ mL but more than about 0 . 0001 Opadry® II Blue . mg/ mL at about room temperature . In some embodiments , the modified -release dosage form In some embodiments , the salt has an aqueous solubility comprises a core tablet and a coating, wherein the weight to 60 of less than about 50 mg /mL but more than about 0 .0001 weight ratio of the core tablet to the coating is about 20 : 1 ; mg/ mL at about room temperature . and wherein the core tablet comprises : about 7 % (R )- 8 - In some embodiments , the salt has an aqueous solubility chloro - 1- methyl - 2 ,3 ,4 , 5 -tetrahydro -1H -3 -benzazepine of less than about 25 mg /mL but more than about 0 .0001 hydrochloride salt hemihydrate , Form III ; about 22 . 5 % mg/ mL at about room temperature . mannitol; about 50 % (hydroxypropyl ) methyl cellulose ; 65 In some embodiments , the salt has an aqueous solubility about 20 % microcrystalline cellulose ; and about 0 . 5 % mag - of less than about 10 mg/mL but more than about 0 .0001 nesium sterate ; and the coating comprises Opadry® II Blue . mg/ mL at about room temperature . US 10 ,226 ,471 B2 27 28 In some embodiments , the salt has an aqueous solubility In some embodiments , the salt is (R ) -8 -chloro - 1 -methyl of less than about 5 mg/ mL but more than about 0 . 0001 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine maleate salt. mg/ mL at about room temperature . In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl In some embodiments , the salt is selected from : ( R ) - 8 - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine fumarate salt . chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine 5 hydroiodide salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro In some embodiments , the salt is (R )- 8 -chloro -1 -methyl 1H - 3 -benzazepine maleate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine hemifumarate salt . 4 ,5 - tetrahydro - 1H - 3 -benzazepine fumarate salt ; (R ) - 8 In some embodiments , the salt is ( R )- 8 -chloro - 1 -methyl chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H -3 -benzazepine 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine orotate salt . hemifumarate salt; (R ) - 8 -chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetra - 10 In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl hydro -1H - 3 -benzazepine orotate salt ; ( R ) - 8 - chloro - 1 - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine orotate salt hydrate . methyl- 2 ,3 , 4 ,5 - tetrahydro - 1H - 3 -benzazepine orotate salt ; In some embodiments , the salt is ( R )- 8 -chloro - 1 -methyl ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 2, 3 ,4 ,5 - tetrahydro - 1H -3 -benzazepine di- 4 -acetamidobenzo zazepine di- 4 -acetamidobenzoate salt ; ( R ) - 8 - chloro - 1 ate salt -cocrystal methyl ethyl ketone solvate . methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine trans- cinna - 15 mate salt ; ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 In some embodiments , the salt is ( R ) - 8 - chloro - 1 - methyl benzazepine heminapadisilate salt ; ( R ) - 8 - chloro - 1 -methyl 2, 3 ,4 ,5 - tetrahydro - 1H - 3 -benzazepine trans -cinnamate salt . 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine ( + )- mandelate salt ; In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl ( R ) -8 - chloro - 1 -methyl - 2 ,3 , 4 ,5 -tetrahydro - 1H -3 -ben 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine heminapadisilate salt . zazepine hemipamoate salt and pharmaceutically acceptable 20 In some embodiments , the salt is ( R ) -8 -chloro - 1- methyl hydrates and solvates thereof. 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine heminapadisilate salt In some embodiments , the salt is selected from : (R ) - 8 - solvate 1 . chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine In some embodiments , the salt is ( R ) - 8 -chloro - 1 - methyl hydroiodide salt; (R )- 8 -chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 2, 3 , 4 ,5 - tetrahydro - 1H -3 - benzazepine heminapadisilate salt 1H - 3 - benzazepine maleate salt ; ( R ) -8 - chloro - 1 -methyl -2 , 3 , 25 solvate 2 . 4 , 5 - tetrahydro - 1H - 3 -benzazepine fumarate salt ; (R ) - 8 chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine In some embodiments , the salt is ( R )- 8 - chloro - 1- methyl hemifumarate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra 2 , 3 ,4 ,5 - tetrahydro - 1H -3 -benzazepine ( + )- mandelate salt hydro - 1H - 3 -benzazepine orotate salt ; ( R )- 8 -chloro - 1 hydrate . methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine trans - cinna - 30 In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl mate salt : ( R ) - 8 - chloro - 1 -methyl - 2 . 3 . 4. 5 -tetrahydro - 1H -3 - 2 , 3 , 4 ,5 - tetrahydro - 1H - 3 -benzazepine hemipamoate salt benzazepine heminapadisilate salt ; and pharmaceutically hydrate . acceptable hydrates and solvates thereof. Adverse Events In some embodiments , the salt is selected from : ( R )- 8 The safety of Compound 1 has been evaluated in three chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine 35 randomized , double -blind , placebo - controlled trials , one of hydroiodide salt ; (R )- 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 2 vears duration (“ BLOOM ” trial) and two of 1 year 1H - 3 -benzazepine maleate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , duration ( “ BLOSSOM ” and “ BLOOM -DM ” trials ) . A total 4 , 5 -tetrahydro - 1H - 3 -benzazepine fumarate salt ; ( R ) -8 - of 3451 patients were exposed to Compound 1 10 mg twice chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine daily for up to 1 year ; 571 patients were exposed for up to hemifumarate salt; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetra - 40 2 years ; and an additional 896 patients were exposed to hydro - 1H - 3 -benzazepine orotate salt ; ( R ) - 8 - chloro - 1 Compound 1 10 mg once daily for up to 1 year . The methyl- 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine orotate salt BLOOM -DM study included only patients with type 2 hydrate; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 diabetes mellitus ; BLOOM and BLOSSOM excluded benzazepine di - 4 -acetamidobenzoate salt - cocrystal methyl patients with diabetes . ethyl ketone solvate ; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra - 45 hydro - 1H - 3 -benzazepine trans - cinnamate salt; ( R ) - 8 The discontinuation rate due to adverse reaction was 7 . 1 % chloro -1 -methyl - 2, 3 ,4 , 5 -tetrahydro - 1H -3 -benzazepine for non -diabetic patients and 8 . 6 % for patients with type 2 heminapadisilate salt; (R )- 8 -chloro - 1- methyl - 2 ,3 ,4 , 5 -tetra diabetes receiving Compound 1. The most common adverse hydro - 1H -3 -benzazepine heminapadisilate salt solvate 1 ; reactions leading to discontinuation more often among Com ( R ) - 8 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben - 50 pound 1 treated patients than placebo were headache ( 1 . 3 % zazepine heminapadisilate salt solvate 2 ; ( R ) - 8 - chloro - 1 vs. 0 . 8 % ), depression (0 . 9 % vs. 0 . 5 % ) and dizziness (0 .7 % methyl- 2 , 3 ,4 , 5 -tetrahydro - 1H - 3 -benzazepine ( + )- mandelate vs. 0 .2 % ). salt hydrate ; (R ) -8 - chlorohloro - 1- methylmethyl -2 . , 3 .,45 4 , 5 - tetrahydro -- 1H - Because clinical trials are conducted under widely vary 3 -benzazepine hemipamoate salt hydrate . ing conditions, adverse reaction rates observed in the clini In some embodiments , the salt is selected from : ( R ) - 8 - 55 cal trials of a drug cannot be directly compared to rates in the chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine oro clinical trials of another drug and may not reflect the rates tate salt hydrate ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - observed in practice . 1H - 3 -benzazepine di - 4 -acetamidobenzoate salt - cocrystal The most common adverse reactions for non -diabetic methyl ethyl ketone solvate ; ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - patients treated with Compound 1 compared to placebo were tetrahydro - 1H - 3 -benzazepine heminapadisilate salt solvate 60 headache , upper respiratory tract infection , nasopharyngitis , 1 ; ( R ) - 8 -chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben - dizziness , and nausea . The most common adverse reactions zazepine heminapadisilate salt solvate 2 ; ( R ) - 8 - chloro - 1 - for diabetic patients were hypoglycemia , headache , back methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine ( + ) -mandelate pain , nasopharyngitis, and nausea . Adverse events thatwere salt hydrate ; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - reported by 25 % of patients and were more frequently 3 -benzazepine hemipamoate salt hydrate . 65 reported by patients taking Compound 1 compared to pla In some embodiments , the salt is ( R )- 8 - chloro - 1 -methyl - cebo are summarized in Table A (BLOOM and BLOSSOM ) 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine hydroiodide salt. and Table B ( BLOOM DM ). US 10 ,226 ,471 B2 29 30 TABLE A wherein the individual to whom the modified - release dosage form , salt or pharmaceutical composition of the present Adverse Events Reported by 25 % of Compound 1 Patients invention is administered experiences at least one adverse and More Commonly than with Placebo in BLOOM and BLOSSOM event selected from the adverse events shown in Table A and Number of patients % Table B . Compound 1 10 mg BID Placebo In some embodiments , the adverse event is selected from Adverse Event N = 3195 N = 3185 headache, fatigue , nausea , constipation , dry mouth , and dizziness . Headache 537 ( 16 . 8 ) 321 ( 10 . 1 ) Upper respiratory 439 (13 . 7 ) 391 ( 12 . 3 ) 10 In some embodiments, the adverse event is headache . tract infection In some embodiments , the adverse event is upper respi Nasopharyngitis 414 ( 13 . 0 ) 381 ( 12 . 0 ) ratory tract infection . Dizziness 270 ( 8 . 5 ) 122 ( 3 . 8 ) Nausea 264 ( 8 . 3 ) 170 ( 5 . 3 ) In some embodiments, the adverse event is dizziness . Fatigue 229 ( 7 . 2 ) 114 ( 3 . 6 ) In some embodiments , the adverse event is nausea . Urinary tract 207 ( 6 . 5 ) 171 ( 5 . 4 ) 15 In some embodiments , the adverse event is fatigue . infection In some embodiments, the adverse event is urinary tract Diarrhea 207 ( 6 . 5 ) 179 ( 5 . 6 ) Back pain 201 (6 . 3 ) 178 ( 5 . 6 ) infection . Constipation 186 ( 5 . 8 ) 125 ( 3 . 9 ) In some embodiments , the adverse event is diarrhea . Dry mouth 169 ( 5 . 3 ) 74 ( 2 . 3 ) In some embodiments , the adverse event is back pain . 20 In some embodiments , the adverse event is constipation . In some embodiments , the adverse event is dry mouth . TABLE B In some embodiments , the adverse event is nasopharyn gitis . Adverse Events Reported by 25 % of Compound 1 Patients and More Commonly than with Placebo In some embodiments , the adverse event is hypoglycemia in BLOOM - DM ( Patients with Type 2 Diabetes ) 25 ( including asymptomatic ). In some embodiments , the adverse event is cough . Number of patients ( % ) In some embodiments , the adverse event is hypoglycemia , symptomatic . Compound 1 10 mg BID Placebo In some embodiments, the adverse event is gastroenteritis Adverse Event N = 3195 N = 3185 - 30 viral. Hypoglycemia 75 ( 29. 3 ) 53 (21 . 0 ) In some embodiments , the adverse event is influenza . ( including asymptomatic ) Headache 37 ( 14 . 5) 18 ( 7 . 1 ) In some embodiments , the adverse event is procedural Back pain 30 (11 . 7 ) 20 ( 7 . 9 ) pain . Nasopharyngitis 29 ( 11 . 3 ) 25 ( 9 . 9 ) In some embodiments , the adverse event is hypertension . Nausea 24 ( 9 . 4 ) 20 ( 7 . 9 ) 35 Salts of the Present Invention Urinary tract infection 23 (9 .0 ) 15 ( 6 . 0 ) Cough 21 ( 8 . 2 ) 11 ( 4 . 4 ) The present invention is directed , inter alia , to certain Hypoglycemia , symptomatic 19 ( 7 . 4 ) 16 (6 .3 ) solid , stable , and readily isolable salts of ( R )- 8 -chloro - 1 Fatigue 19 ( 7 . 4 ) 10 (4 .0 ) methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine and crystalline Gastroenteritis viral 18 ( 7 . 0 ) 11 (4 .4 ) forms thereof. The solid state properties of the crystalline Dizziness 18 ( 7 . 0 ) 16 (6 . 3 ) 40 forms of the present invention are summarized infra . Influenza 15 ( 5 . 9 ) 13 (5 .2 ) Procedural pain 13 ( 5 . 1 ) 5 ( 2 . 0 ) In the course of preparing the salts of the present inven Hypertension 13 ( 5 . 1 ) 8 (3 . 2 ) tion , many counterions commonly used in the pharmaceu tical industry ( see e . g . Berge , et al. , Journal of Pharmaceu tical Sciences, 66 : 1 - 19 ( 1977 ) ) were investigated . Acetate , One aspect of the present invention pertains to methods of 45 DL - lactate , ascorbate , D - gluconate , besylate , napsylate , treatment of the present invention wherein the individual to tosylate , isethionate , dichloroacetate , benzoate , esylate , gen whom the modified -release dosage form of the present tisate , hippurate , lactobionate , xinafoate , and sebacate salts invention is administered experiences at least one adverse of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben event selected from the adverse events shown in Table A and zazepine were prepared , but in contrast to the crystalline Table B . 50 salts of the present invention , all of these failed to crystal One aspect of the present invention pertains to methods of lize . treatment of the present invention wherein the individual to One aspect of the present invention pertains to a salt whom the salt or a pharmaceutical composition of the selected from : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro present invention is administered experiences at least one 1H - 3 -benzazepine hydroiodide salt , ( R ) - 8 - chloro - 1 -methyl adverse event selected from the adverse events shown in 55 2 , 3 , 4 ,5 -tetrahydro - 1H - 3 -benzazepine maleate salt, ( R ) - 8 Table A and Table B . chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine One aspect of the present invention pertains to the use of fumarate salt; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro salts or pharmaceutical compositions of the present inven - 1H - 3 -benzazepine hemifumarate salt ; ( R )- 8 -chloro - 1 tion in the manufacture of a medicament for weight man - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine orotate salt ; agement in an individual, wherein the individual to whom 60 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben the salt or a pharmaceutical composition of the present zazepine orotate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 ,5 -tetra invention is administered experiences at least one adverse hydro - 1H - 3 -benzazepine di - 4 -acetamidobenzoate salt; ( R ) event selected from the adverse events shown in Table A and 8 -chloro - 1 -methyl - 2 ,3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine Table B . trans - cinnamate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra One aspect of the present invention pertains to modified - 65 hydro - 1H - 3 -benzazepine heminapadisilate salt ; ( R ) - 8 release dosage forms, salts , or pharmaceutical composition chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( + ) of the present invention for use in a method of treatment, mandelate salt; (R ) - 8 -chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro US 10 , 226 ,471 B2 31 32 1H - 3 -benzazepine hemipamoate salt and pharmaceutically One aspect of the present invention pertains to ( R )- 8 acceptable hydrates and solvates thereof. chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine di- 4 One aspect of the present invention pertains to a salt acetamidobenzoate salt - cocrystal methyl ethyl ketone sol selected from : (R ) - 8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 -tetrahydro vate . 1H - 3 - benzazepine hydroiodide salt, ( R ) - 8 - chloro - 1 -methyl - 5 One aspect of the present invention pertains to ( R ) - 8 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine maleate salt , ( R ) - 8 chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine trans- cinnamate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetra fumarate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro hydro - 1H - 3 -benzazepine heminapadisilate salt . 1H - 3 -benzazepine hemifumarate salt ; (R ) -8 -chloro -1 - One aspect of the present invention pertains to (R )- 8 methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine orotate salt ; " chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben - heminapadisilate salt solvate 1 . zazepine trans - cinnamate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 ,4 , One aspect of the present invention pertains to ( R )- 8 5 - tetrahydro - 1H - 3 - benzazepine heminapadisilate salt; and chloro - 1 -methyl - 2, 3 , 4 ,5 - tetrahydro - 1H - 3 -benzazepine pharmaceutically acceptable hydrates and solvates thereof. 15 heminapadisilate salt solvate 2 . One aspect of the present invention pertains to a salt One aspect of the present invention pertains to ( R ) - 8 selected from : ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( + ) 1H - 3 -benzazepine hydroiodide salt, ( R ) - 8 - chloro - 1 -methyl mandelate salt hydrate . 2 ,3 , 4, 5 -tetrahydro - 1H - 3 -benzazepine maleate salt , (R )- 8 - One aspect of the present invention pertains to (R )- 8 chloro - 1- methyl - 2 ,3 ,4 , 5 -tetrahydro -1H -3 -benzazepine 20 chloro -1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H - 3 -benzazepine fumarate salt ; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - hemipamoate salt hydrate . 1H - 3 -benzazepine hemifumarate salt; (R ) -8 -chloro - 1 - In some embodiments , the terms “ (R ) - 8 -chloro - 1 -methyl methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine orotate salt ; 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine or a pharmaceutically ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben acceptable salt , solvate , or hydrate thereof” and “ ( R ) - 8 zazepine orotate salt hydrate ; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 25 chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine , and 5 - tetrahydro - 1H - 3 -benzazepine di- 4 - acetamidobenzoate pharmaceutically acceptable salts , solvates, and hydrates salt -cocrystal methyl ethyl ketone solvate ; (R )- 8 -chloro -1 thereof” as used herein encompass any one of the following salts , or a Markush group comprising any combination of the methyl- 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine trans- cinna following salts : mate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H -v 3 30 (R )- 8 -chloro - 1 -methyl - 2, 3 ,4 , 5 -tetrahydro - 1H - 3 -ben benzazepine heminapadisilate salt ; ( R ) - 8 - chloro - 1 -methyl - 30 zazepine ( 1S ) - ( + ) - 10 -camsylate salt ; 2 , 3 ,4 , 5 - tetrahydro - 1H - 3 -benzazepine heminapadisilate salt ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben solvate 1 ; (R )- 8 - chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H - 3 zazepine hemi- L -malate salt ; benzazepine heminapadisilate salt solvate 2 ; ( R ) -8 -chloro ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( + ) -mande 35 zazepine L -glutamate salt; late salt hydrate ; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro ( R )- 8 -chloro - 1 -methyl - 2 , 3 ,4 ,5 -tetrahydro - 1H - 3 - ben 1H - 3 -benzazepine hemipamoate salt hydrate . zazepine L - aspartate salt ; One aspect of the present invention pertains to ( R ) - 8 ( R ) -8 - chloro - 1 -methyl - 2, 3 ,4 ,5 - tetrahydro - 1H -3 -ben chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine oro - zazepine hemimucate salt : tate salt hydrate ; (R )- 8 -chloro - 1 -methyl - 2, 3 ,4 , 5 - tetrahydro - 40 ( R )- 8 -chloro - 1 -methyl - 2 ,3 ,4 , 5 - tetrahydro - 1H -3 -ben 1H - 3 - benzazepine di - 4+ -- acetamidobenzoate salt - cocrystal zazepine pyroglutamate salt ; methyl ethyl ketone solvate ; (R ) -8 -chloro - 1- methyl - 2 ,3 ,4 ,5 - ( R ) -8 - chloro - 1 -methyl - 2 ,3 ,4 ,5 - tetrahydro - 1H - 3 -ben tetrahydro - 1H - 3 -benzazepine heminapadisilate salt solvate zazepine glucuronate salt; and 1 ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben zazepine heminapadisilate salt solvate 2 ; ( R ) - 8 - chloro - 1 - 45 zazepine di -camphorate salt ; methyl- 2 , 3 , 4 ,5 - tetrahydro - 1H - 3 - benzazepine ( + ) -mandelate ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 ,5 - tetrahydro - 1H - 3 -ben salt hydrate ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro - 1H zazepine bisulfate salt ; 3 -benzazepine hemipamoate salt hydrate . ( R ) -8 - chloro - 1 -methyl - 2, 3 ,4 ,5 - tetrahydro - 1H -3 -ben zazepine hemisulfate salt; One aspect of the present invention pertains to ( R ) - 8 50 (R )- 8 -chloro - 1 -methyl - 2, 3 ,4 , 5 -tetrahydro - 1H - 3 -ben chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - benzazepine zazepine mesylate salt ; hydroiodide salt. e . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben One aspect of the present invention pertains to (R ) -8 zazepine hydrobromide salt ; chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro - 1H - 3 -benzazepine ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben maleate salt. . 55 zazepine nitrate salt; One aspect of the present invention pertains to (R )- 8 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro - 1H - 3 -benzazepine zazepine sesqui - oxalate salt - cocrystal ; fumarate salt . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben One aspect of the present invention pertains to ( R ) -8 zazepine adipate salt ; chloro - 1 -methyl - 2 , 3 ,4 , 5 -tetrahydro - 1H - 3 -benzazepine 60 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben hemifumarate salt. zazepine malonate salt ; One aspect of the present invention pertains to (R ) -8 (R )- 8 - chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H - 3 -ben chloro - 1 -methyl - 2 ,3 , 4, 5 -tetrahydro -1H -3 -benzazepine oro - zazepine hemimalonate salt ; tate salt . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben One aspect of the present invention pertains to ( R ) - 8 - 65 zazepine glycolate salt ; chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine oro - ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben tate salt hydrate . zazepine hemi- edisylate salt ; US 10 ,226 ,471 B2 33 34 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben zazepine phosphate salt ; zazepine oxoglutarate salt solvate . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben The preceding salts were prepared and characterized zazepine citrate salt; using the following experimental procedures and physico (R )- 8 -chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H -3 - ben 5 chemical data . zazepine hemi- oxalate salt; ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben zazepine ( 1S ) - ( + ) - 10 - camsylate salt was prepared by the zazepine succinate salt ; and dropwise addition of 1 mole equivalent of ~ 3 .6 M aqueous (R ) - 8 -chloro - 1 -methyl - 2, 3, 4 ,5 - tetrahydro - 1H -3 -ben ( 1S ) - ( + ) - 10 - camphorsulfonic acid to a solution of ( R ) - 8 zazepine oxoglutarate salt; and pharmaceutically acceptable 10 chloro -1 -methyl - 2 ,3 , 4, 5 - tetrahydro - 1H - 3 -benzazepine in solvates and hydrates thereof. acetonitrile with vigorous stirring Immediate precipitation In some embodiments , the terms “ ( R ) - 8 - chloro - 1 -methyl - was observed and the solid was collected by filtration and 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine or a pharmaceutically washed with isopropyl alcohol. ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 , acceptable salt, solvate , or hydrate thereof” and “ ( R ) - 8 - 4 , 5 - tetrahydro - 1H - 3 -benzazepine (1S ) - ( + ) - 10 - camsylate chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine , and 15 salt had an extrapolated melting onset temperature by DSC pharmaceutically acceptable salts , solvates , and hydrates of about 176° C . thereof” as used herein encompass any one of the following (R )- 8 - Chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H - 3 -ben salts , or a Markush group comprising any combination of the zazepine hemi-L -malate salt was prepared by the dropwise following salts : addition of L -malic acid ( 0 . 5 eq . ), either in solution in hot (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben 20 MeOH or as a solid , to a solution of ( R ) - 8 - chloro - 1 -methyl zazepine ( 1S ) - ( + ) - 10 - camsylate salt ; 2 , 3 , 4 ,5 -tetrahydro - 1H - 3 -benzazepine in isopropyl acetate . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben The mixture was heated to - 60° C . and held at that tem zazepine hemi- L -malate salt ; perature for ~ 1 h . The mixture was then allowed to cool to ( R ) -8 -chloro - 1 -methyl - 2, 3 ,4 ,5 - tetrahydro - 1H -3 - ben room temperature and stirred for 1 - 3 days . The solid product zazepine L - glutamate salt ; 25 was isolated by vacuum filtration and dried on the filter or (R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben in an oven at 40° C . ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra zazepine L - aspartate salt ; hydro - 1H - 3 -benzazepine hemi- L -malate salt had an (R ) -8 - chloro - 1- methyl - 2 , 3 ,4 ,5 - tetrahydro - 1H -3 -ben extrapolated melting onset temperature by DSC of 155 - 156° zazepine hemimucate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 30 ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben zazepine pyroglutamate salt ; zazepine L - glutamate salt was prepared by addition of ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben L - glutamic acid ( 0 . 5 - 1 eq .) in hot EtOH /H20 ( ~ 2 : 1 ) to a zazepine glucuronate salt ; solution of (R )- 8 - chloro - 1- methyl - 2 ,3 , 4, 5 - tetrahydro - 1H - 3 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben benzazepine in isopropyl acetate , followed by evaporation zazepine di- camphorate salt solvate ; 35 of the solvent overnight to produce a solid . The solid was ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben slurried in isopropyl acetate and then isolated by filtration . zazepine bisulfate salt ; Alternatively , (R )- 8 - Chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 1H - 3 -benzazepine L - glutamate salt was prepared by addi zazepine hemisulfate salt hydrate ; tion of a solution of L - glutamic acid ( 1 eq . ) in hot H2O to ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 40 a solution of ( R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H zazepine mesylate salt ; 3 -benzazepine . The product crystallized without the need for ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben evaporation of the solvent. ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 zazepine hydrobromide salt hemihydrate; tetrahydro - 1H - 3 - benzazepine L - glutamate salt had an ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben extrapolated melting onset temperature by DSC of about zazepine nitrate salt; 45 187° C . (R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben zazepine sesqui- oxalate salt -cocrystal ; zazepine L - aspartate salt was prepared by addition of a (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben solution of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 zazepine adipate salt ; benzazepine in either acetone or acetonitrile to one equiva ( R )- 8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro -1H - 3 -ben 50 lent of aspartic acid solid . The mixture was heated to 50° C . zazepine malonate salt; then slow - cooled and stirred overnight. ( R ) - 8 - Chloro - 1 (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben methyl - 2 , 3 ,4 , 5 - tetrahydro - 1H - 3 -benzazepine L - aspartate zazepine hemimalonate salt ; salt had an extrapolated melting onset temperature by DSC ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben of about 174° C . zazepine glycolate salt ; 55 ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben zazepine hemimucate salt was synthesized from ( R ) - 8 zazepine hemi- edisylate salt ; chloro - 1- methyl - 2 ,3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine ( 2 ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben equivalents ) and mucic acid ( 1 equivalent ) in THF, acetone zazepine phosphate salt ; or IPA ( ~ 10 mg/ mL ) with 4 % water. ( R ) - 8 - Chloro - 1 -methyl (R )- 8 -chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H - 3 -ben 60 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine hemimucate salt had zazepine citrate salt hemihydrate ; an extrapolated melting onset temperature by DSC of about (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 208° C . zazepine hemi- oxalate salt ; ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben (R )- 8 -chloro - 1 -methyl - 2 ,3 , 4, 5 -tetrahydro - 1H -3 -ben zazepine glucuronate salt was prepared by addition of a zazepine succinate salt ; 65 molar equivalent of D - glucuronic acid to a solution of (R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben zazepine oxoglutarate salt; and zazepine in isopropanol, acetonitrile , ethyl acetate , or US 10 , 226 , 471 B2 35 36 acetone at 60° C . D - glucuronic acid , dissolved in the cor - zazepine mesylate salt had an extrapolated melting onset responding solvent at 60° C ., was added dropwise with temperature by DSC of about 178° C . vigorous stirring . Precipitation occurred immediately and (R )- 8 - Chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H - 3 -ben the suspension was allowed to cool and stir overnight. The zazepine hydrobromide salt hemihydrate was prepared by resulting solid was recovered by filtration and dried in a 5 the dropwise addition of one equivalent of aqueous HBr fume hood overnight. ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra - ( ~ 48 % ) to a solution of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tet hydro - 1H - 3 -benzazepine glucuronate salt had an extrapo rahydro - 1H - 3 -benzazepine free base in isopropyl acetate , lated melting onset temperature by DSC of about 164° C . acetonitrile , or ethyl acetate with vigorous stirring . The (R ) -8 -Chloro - 1- methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H - 3 -ben product readily precipitated from the reaction in isopropyl zazepine pyroglutamate salt was prepared by combining one 10 acetate . In acetonitrile the solvent was evaporated to near equivalent of pyroglutamic acid with ( R ) - 8 - chloro - 1 - dryness to obtain a solid . In ethyl acetate , seeds were added methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine in ethyl and the reaction was allowed to stir unstoppered to initiate acetate at 60° C . then cooling slowly and stirring overnight. crystallization . The reaction was then closed and stirring was The resulting white solid was isolated by filtration and dried . continued to afford a yellow suspension . The suspension was ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 15 filtered and the solid was washed with cold ethyl acetate . zazepine pyroglutamate salt had an extrapolated melting The resulting white solid was under nitrogen at - 38° C ., and onset temperature by DSC of about 139° C . held overnight at 25° C . / 75 % RH . ( R ) - 8 -Chloro - 1 -methyl (R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine hydrobromide salt zazepine di- camphorate salt solvate was prepared by com hemihydrate had an extrapolated dehydration onset tempera bining equal molar amounts of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 20 ture by TGA of about 72 . 5° C . 4 , 5 - tetrahydro - 1H - 3 -benzazepine and ( 1R , 3S ) - ( + ) ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben camphoric acid in ethyl acetate with 4 % water . The solution zazepine nitrate salt was prepared by dropwise addition of was heated to 50° C . then slowly cooled . Upon cooling the aqueous HNO3 to a solution of (R ) -8 -chloro - 1 -methyl - 2 ,3 , sample was a clear solution and did not change after addition 4 , 5 -tetrahydro - 1H - 3 - benzazepine free base in isopropyl of MTBE . The sample was evaporated to a clear oil which 25 acetate or acetonitrile with vigorous stirring. ( R ) - 8 - Chloro formed a white solid after standing at room temperature . 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine nitrate salt ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben had an extrapolated melting onset temperature by DSC of zazepine di- camphorate salt had an extrapolated melting about 124° C . onset temperature by DSC of about 90° C . ( R ) -8 - Chloro - 1 -methyl - 2 ,3 , 4, 5 -tetrahydro - 1H -3 -ben (R )- 8 - Chloro -1 -methyl - 2 ,3 ,4 ,5 -tetrahydro - 1H - 3 -ben - 30 zazepine sesqui- oxalate salt -cocrystal was prepared by addi zazepine bisulfate salt was prepared by drop - wise addition tion of oxalic acid ( 0 . 5 eq . ) to a solution of ( R ) - 8 - chloro of 1 mole equivalent of concentrated sulfuric acid to a 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine in isopropyl solution of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - acetate . ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 benzazepine free base in either isopropyl acetate or acetoni benzazepine sesqui- oxalate salt -cocrystal had an initial trile with vigorous stirring . Precipitation occurred immedi- 35 endotherm with an extrapolated onset temperature by DSC ately and the suspension was allowed to stir for 1 to 2 days . of about 105° C . and a second endotherm with an extrapo The resulting solid was recovered by filtration . ( R ) - 8 - lated melting onset temperature by DSC of about 111° C . Chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro - 1H - 3 -benzazepine ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben bisulfate salt had an extrapolated melting onset temperature zazepine adipate salt was prepared by addition of adipic acid by DSC of about 102162° C . 40 (0 . 5 - 1 eq .) in acetone to a solution of ( R ) -8 -chloro - 1 -methyl ( R )- 8 -Chloro - 1 -methyl - 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 -ben 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine at ~ 62° C . Precipita zazepine hemisulfate salt was prepared by the drop -wise tion occurred within 5 min and the suspension was allowed addition of 0 . 5 mole equivalent of concentrated sulfuric acid to cool to ambient temperature with stirring . ( R ) - 8 - Chloro to a solution of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine adipate salt 1H - 3 -benzazepine free base in either isopropyl acetate or 45 had multiple endothermic events by DSC starting at onset acetonitrile with vigorous stirring . Precipitation occurred temperatures between 104° C . and 107° C . immediately and the suspension was allowed to stir for 1 to (R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben 2 days . The resulting yellow solid was recovered by filtra - zazepine malonate salt was prepared by addition of malonic tion . Acetone was added to the solid followed by sufficient acid ( 1 eq . ) to a solution of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 water to cause dispersal ( < 5 % ) . This mixture was slurried 50 tetrahydro - 1H - 3 -benzazepine in isopropyl acetate . ( R ) - 8 for 4 h and the solid was collected by centrifuge filtration Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine ( 10 ,000 rpm for 1 min ) . The filtrate contained an oil droplet malonate salt had an extrapolated melting onset temperature and the filter cake had a small amount of color at the bottom . by DSC of about 143° C . The white upper portion of the filter cake was removed and (R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben air -dried overnight to leave the title salt as a white solid . 55 zazepine hemimalonate salt was prepared by addition of ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben malonic acid ( 0 . 5 eq. ) to a solution of ( R ) - 8 - chloro - 1 zazepine hemisulfate salt had an extrapolated melting onset methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine in isopropyl temperature by DSC of about 79° C . acetate . ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben benzazepine hemimalonate salt had an extrapolated melting zazepine mesylate salt was prepared by the dropwise addi- 60 onset temperature by DSC of 135 - 136° C . tion of one equivalent ofmethanesulfonic acid (99 . 5 % ) to a ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben solution of ( R ) - 8 - chloro - 1 -methyl - 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 - zazepine glycolate salt was prepared by the addition of one benzazepine free base in acetonitrile , or isopropyl acetate equivalent of glycolic acid to a solution of ( R ) - 8 - chloro - 1 with vigorous stirring . Crystallization occurred either imme - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine in ethyl diately or within 24 hours after the solution was heated to 65 acetate or acetone at 60° C . Glycolic acid , at 60° C ., was ~ 60° C . and then allowed to cool to RT while stirring . added dropwise , in the corresponding solvent, with vigorous ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben stirring . Precipitation occurred immediately and the suspen US 10 ,226 ,471 B2 37 38 sion was allowed to cool and stir overnight. The resulting ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben solid was recovered by filtration and air - dried in a fumewe zanzazepine in acetonitrile at 60° C . a -Oxo - glutaric acid in hood overnight. ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro acetonitrile at 60° C . was added dropwise with vigorous 1H - 3 -benzazepine glycolate salt had an extrapolated melting stirring . Precipitation occurred immediately and the suspen onset temperature by DSC of about 138° C . 5 sion was allowed to cool and stir overnight The resulting ( R )- 8 -Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben solid was recovered by filtration and air -dried in a fume zazepine hemi- edisylate salt was prepared by the dropwise hood overnight. ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro addition of 0 . 5 equivalents of aqueous 1 , 2 - ethanedisulfonic 1H - 3 -benzazepine oxoglutarate salt solvate had an extrapo acid dihydrate (~ 3 . 7 M ) to a solution of (R ) - 8 -chloro - 1 methyl- 2 , 3, 4, 5 - tetrahydro - 1H - 3 -benzazepine free base in 10 lated desolvation onset temperature by DSC of about 91° C ., either acetonitrile or isopropyl acetate with vigorous stirring and a second endotherm with an extrapolated onset tem Immediate precipitation was observed . The solid obtained perature by DSC of about 113° C . was washed with isopropyl alcohol and allowed to dry on the One aspect of the present invention pertains to methods filter . ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben for weight management comprising administering to an zazepine hemi- edisylate salt had an extrapolated meltinging 1515 individualIf in need thereof, a therapeutically effective onset temperature by DSC of about 298° C . amount of a salt of the present invention . ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben One aspect of the present invention pertains to uses of zazepine phosphate salt was prepared by dropwise addition salts or pharmaceutical compositions of the present inven of ortho - phosphoric acid ( 85 % ) ( 0 . 5 - 1 mole equivalent) to a tion , in the manufacture of a medicament for weight man solution of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - 20 agement in an individual. benzazepine free base in isopropyl acetate or acetonitrile In some embodiments , the weight management comprises with vigorous stirring Immediate precipitation was observed one or more of: weight loss, and maintenance of weight loss . in all experiments . Initially amorphous materialwas slurried In some embodiments , the weight management comprises in acetone ; initially crystalline material was slurried / ripened one or more of: weight loss , maintenance of weight loss , in n - propanol for 3 days . ( R ) - 8 - Chloro - 1 -methyl - 2 , 3 ,4 , 5 - 25 decreased food consumption , increasing meal -related sati tetrahydro - 1H - 3 - benzazepine phosphate salt had an extrapo - ety , reducing pre -meal hunger, and reducing intra -meal food lated melting onset temperature by DSC of about 208° C . intake . ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the medicament is used as an zazepine citrate salt hemihydrate was prepared by dropwise adjunct to diet and exercise . addition of 1 mole equivalent of citric acid in hot MeOH to 30 In some embodiments , the individual in need of weight a solution of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H management is selected from : an obese patient with an 3 -benzazepine in isopropyl acetate. Precipitation occurred initial body mass index 230 kg /m ” ; an overweight patient spontaneously . ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetrahydro with an initial body mass index 227 kg /m² in the presence 1H - 3 -benzazepine citrate salt hemihydrate had a dehydra - of at least one weight related comorbid condition ; and an tion onset temperature by DSC of about 80° C . 35 overweight patient with an initial body mass index 27 ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben kg /m² in the presence of at least one weight related comorbid zazepine hemi-oxalate salt was prepared by dropwise addi condition ; wherein the weight related co -morbid condition is tion of 1 mole equivalent of oxalic acid as a solid or as a selected from : hypertension , dyslipidemia , cardiovascular solution in MeOH (~ 2 . 5 M ) to a solution of ( R ) - 8 -chloro - disease , glucose intolerance , and sleep apnea . 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine in isopropyl 40 In some embodiments , the medicament is used in a acetate . ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - method of the present invention . benzazepine hemi- oxalate salt had an extrapolated melting I n some embodiments , the medicament is a modified onset temperature by DSC of about 212° C . release dosage form of the present invention . (R ) - 8 - Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the medicament is used in com zazepine succinate salt was prepared by the addition of 45 bination with a second anti -obesity agent. succinic acid ( 0 . 5 - 1 eq .) in hot EtOH to a solution of In some embodiments , the second anti -obesity agent is ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben selected from : chlorphentermine, clortermine, phenpenter zazepine in isopropyl acetate . After overnight stirring , a mine , and phentermine , and pharmaceutically acceptable solid was recovered by suction filtration and washed in salts , solvates , and hydrates thereof. isopropyl acetate . ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 ,4 , 5 - tetra - 50 In some embodiments , the medicament is used in com hydro - 1H - 3 -benzazepine succinate salt had an extrapolated bination with an anti - diabetes agent. melting onset temperature by DSC of about 179 . 1° C . In some embodiments , the medicament is used in com (R )- 8 -Chloro - 1 -methyl -2 , 3 ,4 ,5 - tetrahydro - 1H -3 -ben bination with metformin . zazepine oxoglutarate salt was prepared by addition of one One aspect of the present invention pertains to the use of equivalent of a - oxo - glutaric acid to a solution of ( R ) - 8 - 55 salts of the present invention in the manufacture of a chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine in medicament for weight management in an individual . ethyl acetate at 60° C . a - Oxo - glutaric acid in ethyl acetate One aspect of the present invention pertains to salts of the at 60° C . was added dropwise with vigorous stirring . Pre - present invention for use in a method of treatment of the cipitation occurred immediately and the suspension was human or animal body by therapy . allowed to cool and stir overnight. The resulting solid was 60 One aspect of the present invention pertains to salts of the recovered by filtration and air - dried in a fume hood over - present invention for use in a method of weight manage night. ( R ) - 8 -Chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - ben - ment. zazepine oxoglutarate salt had an extrapolated melting onset O ne aspect of the present invention pertains to salts of the temperature by DSC of about 115º C . present invention for use in a method of weight loss. (R ) -8 -Chloro - 1 -methyl - 2 ,3 , 4 ,5 - tetrahydro - 1H - 3 - ben - 65 One aspect of the present invention pertains to salts of the zazepine oxoglutarate salt solvate was prepared by addition present invention for use in a method of maintenance of of a molar equivalent of a - oxo - glutaric acid to a solution of weight loss . US 10 , 226 , 471 B2 39 40 One aspect of the present invention pertains to salts of the One aspect of the present invention pertains to salts of the present invention for use in a method of decreasing food present invention for use in a method of weight management consumption in combination with phentermine . One aspect of the present invention pertains to salts of the Formulation present invention for use in a method of increasing meal - 5 For oral drug products , the dosing frequency can be related satiety . reduced by designing a formulation that reduces the drug One aspect of the present invention pertains to salts of the release rate and thereby the rate of input of the drug into present invention for use in a method of reducing pre -meal systemic circulation in order to produce the desired phar hunger. macokinetic profile . In addition to improving patients ' com 10 pliance , such modified -release dosage forms offer the advan One aspect of the present invention pertains to salts of the tages of enhancing therapeutic efficacy , reducing adverse present invention for use in a method of reducing intra -meal effects, and enabling product differentiation . Therefore , over food intake . the past few decades , modified -release technology has been One aspect of the present invention pertains to salts of the increasingly used in clinical development as an enabling present invention for use in a method101 of. weight management 1515 techtechnology for drug - candidate progression . It has been further comprising a reduced -calorie diet . reported that patients ' adherence to the prescribed dosing One aspect of the present invention pertains to salts of the regimen is inversely related to the dosing frequency, espe present invention for use in a method of weightmanagement cially for the management of chronic diseases (Saini S . D . et further comprising a program of regular exercise . al . Effect OfMedication Dosing Frequency On Adherence In One aspect of the present invention pertains to salts of the 20 Chronic Diseases. Am . J . Managed Care . 2009 ; 15 ( 6 ): e22 present invention for use in a method ofweight management e33 ) . further comprising a reduced - calorie diet and a program of Commonly used and commercially viable modified - re regular exercise . lease technologies include hydrophilic /hydrophobic matri One aspect of the present invention pertains to salts of the ces ; polymer -coated pellets and beads pre -loaded with API ; present invention for use in a method of weightmanagement 25 and multilayer tablets . Osmotic pump tablets can achieve in an obese patient with an initial body mass index > 30 much more consistent pump - like release profiles . These may kg /m² . use POLYOXTM ( The Dow Chemical Company ) in the drug One aspect of the present invention pertains to salts of the layer and push layer and may be coated with cellulose present invention for use in a method of weight management acetate and PEG . in an overweight patient with an initial body mass index 227 30 Drug release from these technologies is controlled by one kg / m ^ in the presence of at least one weight related co - or a combination of the following mechanisms: diffusion morbid condition . ( through the pores of a barrier coating layer or a viscous gel One aspect of the present invention pertains to salts of the layer of entangled polymer chains ), osmosis , and polymer present invention for use in a method ofweight management swelling / erosion . Each technology is different with regard to in an overweight patient with an initialbody mass index 227 35 the in vivo performance , release - controlling mechanism , kg /m² in the presence of at least one weight related co - development time and cost, manufacturability , applicability morbid condition selected from : hypertension , dyslipidemia , to the inherent biopharmaceutical properties of the API. cardiovascular disease , glucose intolerance , and sleep apnea . Selection of modified - release technology for a particular One aspect of the present invention pertains to salts of the drug will depend on the dose , solubility, pharmacokinetics , present invention for use in a method of weightmanagement 40 desired in vitro release profile , as well as clinical and in a patient with an initial body mass index 230 kg/ m² . marketing requirements ( e. g ., dosage form type , size , num One aspect of the present invention pertains to salts of the ber of strengths ). present invention for use in a method of weightmanagement Pharmacokinetics simulation can be used in the design in a patient with an initial body mass index 227 kg/ m² . and assessment of modified - release formulation develop One aspect of the present invention pertains to salts of the 45 ment . If the therapeutic dose and human pharmacokinetics present invention for use in a method ofweight management parameters are available for the drug molecule of interest , in a patient with an initial body mass index 227 kg /m² in the the release profile from modified - release formulation can be presence of at least one weight related co -morbid condition projected through simulation , which facilitates the selection One aspect of the present invention pertains to salts of the of modified -release delivery technology , formulation , and present invention for use in a method of weightmanagement 50 expected release profile . in a patient with an initial body mass index 227 kg /m² in the Hydrophilic Swelling Excipients presence of at least one weight related co -morbid condition Among the modified - release technologies, the hydro selected from : hypertension , dyslipidemia , cardiovascular philic polymer matrix is especially widely used due to the disease , glucose intolerance , and sleep apnea . thorough understanding of its release -control mechanism , One aspect of the present invention pertains to salts of the 55 robust formulation , conventional manufacturing process , present invention for use in a method of weight management availability of a wide range of polymers , and flexibility to in a patient with an initial body mass index > 25 kg/ m² . tailor desired release profiles . Commonly used polymers One aspect of the present invention pertains to salts of the include HPMC , high -molecular weight polyethylene oxides , present invention for use in a method ofweight management polyvinylpyrrolidone , and polysaccharides of natural origin in a patient with an initial body mass index > 25 kg / m in the 60 such as Xanthan gum and locust bean gum . presence of at least one weight related co -morbid condition . Typically , a hydrophilic polymer matrix system consists One aspect of the present invention pertains to salts of the of drug, rate - controlling polymers, and other excipients present invention for use in a method of weightmanagement which are homogenously mixed and compressed into a in a patient with an initial body mass index 225 kg/ m² in the tablet . Upon exposure to aqueous medium , the polymer presence of at least one weight related co -morbid condition 65 becomes hydrated and forms a gel layer on the periphery of selected from : hypertension , dyslipidemia , cardiovascular the tablet which modulates further water penetration and disease , glucose intolerance , and sleep apnea . subsequent drug diffusion and release. It has been demon US 10 , 226 , 471 B2 41 42 strated that the drug release rate and kinetics are predomi in the immediate release tablets , Compound 1 , hydrochlo nantly dependent on the rate of gel formation and erosion , ride salt hemihydrate , Form III (as described below ) , gel layer thickness and strength , the solubility of added exceeds 400 mg/ mL in the pH range of 1 to 7 , and is excipients , as well as the solubility of the drug to be classified under the Biopharmaceutics Classification System delivered . (Siepmann J . and Peppas N . A ., Modeling Of 5 as " highly soluble ” . A drug substance is considered highly Drug Release From Delivery Systems Based On Hydroxy - soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 - 7 . 5 . propyl Methylcellulose (HPMC ) . Adv. Drug Deliv. Rev. , Compound 1 , hydrochloride salt hemihydrate , Form III is 2001 ; 48 , 139 -157 ) . Drug release from HMPC tablets is further classified under the Biopharmaceutics Classification controlled by diffusion through the gel layer surrounding theà 10 System as " highly permeable ” . In the absence of evidence tablet. The gel layer thickness and strength are determined suggesting instability in the gastrointestinal tract , a drug by the viscosity and concentration of HPMC . Increase in substance is considered to be highly permeable when the HPMC level leads to the formation of a stronger gel layer , extent of absorption in humans is determined to be 90 % or thus retarding water ingress and drug diffusion . more of an administered dose based on a mass balance Tablet Coating 15 determination or in comparison to an intravenous reference When exposed to aqueous medium , water penetration into dose . hydrophilic polymer matrix tablets is modulated only by The value of Cmor (peak plasma concentration ) from the swelling of the hydrophilic polymer . The release of highly modified - release formulation should not exceed that of the soluble APIs may not be adequately controlled by the immediate - release 10 -mg tablet twice daily ( b . i . d . ) , a for swelling and diffusion mechanism alone . An additional 20 mulation for which safety has been established in phase 3 mechanism may be needed to restrict water ingress into the clinical trials . Release from the modified - release formula tablet and subsequent diffusion of the API. Commonly used tion should be the limiting step for its absorption . strategies include compression coating, multilayer tablet, One aspect of the present invention pertains to modified and functional film coating ( such as enteric coating, release dosage forms comprising a therapeutically effective insoluble coating , and pH -dependent polymer coating ) . 25 amount of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 Functional film coating offers the advantages of robust benzazepine or a pharmaceutically acceptable salt solvate formulation and processing , proven in vivo performance in or hydrate thereof. other commercial products ( e . g ., Wellbutrin XL? ) . The In some embodiments , the modified - release dosage form coating regulates water penetration , core tablet hydration , is a tablet . and API diffusion . Additives such as low -viscosity HPMC 30 In some embodiments , the modified -release dosage form can be added to the coating as pore former. The additive is for use in a method of weight management in an indi dissolves and leaches out of the coating membrane when vidual. exposed to aqueous media , thus generating pores in the In some embodiments , the method comprises a plurality coating membrane . These pores allow water to penetrate of administrations of the modified - release dosage form , with through the coating and be in contact with the core tablet. 35 a frequency wherein the average interval between any two API Solubility sequential the administrations is : at least about 24 hours; or For active pharmaceutical ingredients ( APIs ) having more about 24 hours . than adequate aqueous solubility throughout the Gl- tract pH In some embodiments , the plurality of administrations is : range, dissolution of the API inside a modified -release at least about 30 ; at least about 180 ; at least about 365 ; or at dosage form will be rapid , per the Noyes - Whitney equation : 40 least about 730 . In some embodiments, the method is more efficacious than an immediate - release method for weight management ; dW DA (Cs - C ) = wherein the immediate -release method for weight manage di ment comprises administering to an individual in need 45 thereof, at the frequency , the plurality of administrations of where dW / dt is the dissolution rate (mg / s ); D is the diffusion an immediate - release dosage form comprising the therapeu coefficient ( cm²/ s ) ; A is the surface area of the API ( cm ) ; C , tically effective amount of (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 is the saturated concentration ( or solubility ) in the diffusion tetrahydro - 1H - 3 -benzazepine or a pharmaceutically accept layer around the API; C is the bulk solvent concentration able salt , solvate , or hydrate thereof. (mg /mL ) ; and L is the diffusion layer thickness ( cm ) . For 50 In some embodiments , the method is more efficacious permeable drugs , C > > C , since drug molecules that diffuse than an immediate - release method for weight management; into the GI bulk media are rapidly absorbed . In this case, C wherein the immediate -release method for weight manage can be ignored in the Noyes- Whitney equation and disso - ment comprises administering to an individual in need lution rate becomes proportional to the solubility of the API. thereof, an immediate - release dosage form comprising ( R ) Salt forms with high aqueous solubility may be used in 55 8 - chloro - 1 -methyl - 2 , 3 ,4 , 5 -tetrahydro - 1H - 3 -benzazepine or modified - release dosage forms when formulated with a a pharmaceutically acceptable salt , solvate , or hydrate hydrophilic swelling excipient . A polymer coating may also thereof; and wherein the total plasma exposure of the be used to further modify the release of the API from these individual to (R )- 8 -chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H dosage forms. 3 -benzazepine over the course of the immediate - release In order to develop modified -release formulations of 60 method is equal to or greater than the total plasma exposure Compound 1 that do not rely on hydrophilic swelling and /or of the individual to ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra functional film coating , there is a need for new salt forms hydro - 1H - 3 - benzazepine over the course of the method . with low aqueous solubility . In some embodiments, the plasma concentration of the Immediate Release Tablets ( R ) -8 - chloro - 1- methyl -2 , 3 ,4 ,5 - tetrahydro - 1H -3 -ben An immediate - release , film - coated 10 -mg tablet was 65 zazepine in the individual has a Cmar of: less than about 60 developed for the phase 3 clinical trials and commercializa - ng/ mL ; less than about 40 ng/ mL ; less than about 20 ng/ mL ; tion of Compound 1 (Example 5 ) . The solubility of the API or less than about 10 ng/ mL . US 10 , 226 , 471 B2 43 44 In some embodiments , the Cmax divided by the therapeu about 20 : 1 ; and wherein the core tablet comprises: about 7 % tically effective amount is equal to : less than about 1x10 - 5 ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 ,5 - tetrahydro - 1H - 3 -ben mL - 1 ; less than about 5x10 - mL - 1 ; less than about 1x10 - 6 zazepine hydrochloride salt hemihydrate , Form III ; about mL - 1 ; or less than about 5x10 - 7 mL - 1 . 22. 5 % mannitol; about 50 % (hydroxypropyl )methyl cellu In some embodiments , the Cmor occurs : more than 30 5 lose ; about 20 % microcrystalline cellulose ; and about 0 . 5 % minutes after the administering ; more than 1 hour after the magnesium sterate ; the film coating comprises : about 85 % administering ; or more than 2 hours after the administering . ethyl cellulose ; and about 15 % (hydroxypropyl ) methyl cel In some embodiments , the Cmor occurs : more than 3 hours lulose ; or about 75 % ethyl cellulose ; and about 25 % (hy after the administering ; more than 6 hours after the admin - droxypropyl) methyl cellulose . istering ; or more than 12 hours after the administering . 10 In some embodiments , the modified -release dosage form In some embodiments, the average peak to trough ratio of has a T80 % of: at least 3 h ; at least 6 h ; at least 9 h ; or at the plasma concentration of the ( R ) -8 - chloro - 1 -methyl -2 , 3 , least 12 h . 4 ,5 - tetrahydro - 1H - 3 -benzazepine in the individual is : less In some embodiments , the modified - release dosage form than about 3 : 1 ; less than about 2 : 1 ; less than about 1 . 5 : 1 ; or comprises a salt selected from : a pharmaceutically accept less than about 1 . 1 : 1 . 15 able salt of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 In some embodiments , the modified - release dosage form benzazepine and pharmaceutically acceptable solvates and comprises a salt selected from : ( R ) -8 - chloro - 1 -methyl - 2 , 3 , hydrates thereof, and wherein the salt has an aqueous 4 , 5 - tetrahydro - 1H - 3 -benzazepine hydrochloride and phar solubility of: less than about 200 mg/ mL at about room maceutically acceptable solvates and hydrates thereof. temperature ; less than about 100 mg/ mL at about room In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - 20 temperature ; less than about 50 mg/ mL at about room 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine hydrochloride salt temperature ; less than about 25 mg/ mL at about room hemihydrate , Form III . temperature ; less than about 10 mg/mL at about room In some embodiments , the modified -release dosage form temperature ; or less than about 5 mg/ mL at about room further comprises (hydroxypropyl ) methyl cellulose . temperature . In some embodiments , the modified -release dosage form 25 In some embodiments , the modified -release dosage form further comprises one or more ingredients selected from : comprises a salt selected from : (R )- 8 -chloro -1 -methyl - 2 ,3 , microcrystalline cellulose , mannitol, and magnesium stear - 4 , 5 - tetrahydro - 1H - 3 - benzazepine hydroiodide salt ; ( R ) - 8 ate . chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine In some embodiments , the modified -release dosage form maleate salt; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H further comprises a film coating . 30 3 - benzazepine fumarate salt ; and ( R ) - 8 - chloro - 1 -methyl - 2 , In some embodiments , the film coating comprises a 3 ,4 , 5 - tetrahydro -1H -3 - benzazepine hemifumarate salt ; (R ) water- soluble film coating . 8 -chloro - 1 -methyl -2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine In some embodiments , the film coating comprises ethyl orotate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H cellulose . 3 -benzazepine di- acetamidobenzoate salt- cocrystal; ( R ) - 8 In some embodiments , the film coating further comprises 35 chloro - 1 -methyl - 2, 3 ,4 , 5 - tetrahydro - 1H -3 -benzazepine ( hydroxypropyl) methyl cellulose . trans - cinnamate salt; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra In some embodiments, the ratio of the ethyl cellulose to hydro - 1H - 3 -benzazepine heminapadisilate salt ; ( R ) -8 the (hydroxypropyl )methyl cellulose is : about 75 : 25 ; about chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine ( + ) 80 : 20 ; or about 85 : 15 . mandelate salt ; and ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 In some embodiments , the modified -release dosage form 40 tetrahydro - 1H - 3 - benzazepine hemipamoate salt ; and comprises a core tablet and a film coating ; wherein the core pharmaceutically acceptable solvates and hydrates thereof. tablet comprises : (R )- 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - One aspect of the present invention pertains to modified 1H - 3 -benzazepine hydrochloride salt hemihydrate , Form release dosage forms comprising a therapeutically effective III ; mannitol; (hydroxypropyl ) methyl cellulose ; microcrys dose of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 talline cellulose ; and magnesium sterate ; and the film coat- 45 benzazepine or a pharmaceutically acceptable salt , solvate , ing comprises a water - soluble film coating . or hydrate thereof. In some embodiments , the modified - release dosage form One aspect of the present invention pertains to modified comprises a core tablet and a film coating, wherein the release dosage forms comprising a therapeutically effective weight to weight ratio of the core tablet to the coating is dose of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 about 20 : 1 ; and wherein the core tablet comprises: about 7 % 50 benzazepine or a pharmaceutically acceptable salt , solvate , ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben or hydrate thereof, for use in a method of weight manage zazepine hydrochloride salt hemihydrate , Form III; about ment in an individual. 22. 5 % mannitol; about 50 % (hydroxypropyl ) methyl cellu - One aspect of the present invention pertains to modified lose ; about 20 % microcrystalline cellulose ; and about 0 . 5 % release dosage forms comprising a therapeutically effective magnesium sterate ; and the film coating comprises a water - 55 amount of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 soluble film coating . benzazepine or a pharmaceutically acceptable salt, solvate , In some embodiments , the modified -release dosage form or hydrate thereof. comprises a core tablet and a film coating ; wherein the core In some embodiments , the modified - release dosage form tablet comprises : ( R ) - 8 -chloro - 1 -methyl - 2 ,3 , 4 , 5 -tetrahydro - is a tablet . 1H - 3 -benzazepine hydrochloride salt hemihydrate , Form 60 In some embodiments , the method comprises a plurality III; mannitol ; (hydroxypropyl )methyl cellulose ; microcrys - of administrations of the modified -release dosage form , with talline cellulose ; and magnesium sterate ; and the film coat- a frequency wherein the average interval between any two ing comprises: ethyl cellulose ; and (hydroxypropyl )methyl sequential administrations is at least about 24 hours . cellulose . In some embodiments , the method comprises a plurality In some embodiments , the modified -release dosage form 65 of administrations of the modified - release dosage form , with comprises a core tablet and a film coating , wherein the a frequency wherein the average interval between any two weight to weight ratio of the core tablet to the coating is sequential administrations is about 24 hours . US 10 , 226 ,471 B2 45 46 In some embodiments , the plasma concentration of the In some embodiments , the AUCiast divided by the thera ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben peutically effective amount is equal to at least about 1x10 - 2 zazepine in the individual has a Cmar of less than about 60 h /mL . ng /mL . In some embodiments , the AUCjast divided by the Cmax is In some embodiments , the plasma concentration of the 5 equal to at least about 5 h . (R )- 8 - chloro -1 -methyl - 2 ,3 ,4 ,5 - tetrahydro - 1H -3 -ben In some embodiments , the AUCiast divided by the Cmar is zazepine in the individual has a C . of less than about 40 equalIn some to at embodimentsleast about 10 , theh . AUCiast divided by the Cmax is ng /mL . equal to at least about 15 h . In some embodiments , the plasma concentration of the 10 In some embodiments , the AUCiast divided by the Cmax is ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben equal to at least about 25 h . zazepine in the individual has a Cmax of less than about 20 In some embodiments , the administering results in a min ng/ mL . of at least about 5 ng /mL and a Cmor of less than about 60 . In some embodiments , the plasma concentration of the In some embodiments , the administering results in a min ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 15 of at least about 5 ng /mL and a Cmor of less than about 40 zazepine in the individual has a Cmax of less than about 10 ng /mL . ng/ mL . In some embodiments , the administering results in a min In some embodiments , the Cmax divided by the therapeu of at least about 5 ng/ mL and a Cmor of less than about 20 tically effective amount is equal to less than about 1x10 ng /mL . mL - 1 . 20 In some embodiments , the administering results in a min In some embodiments , the Cmax divided by the therapeu - of at least about 5 ng/ mL and a Cmax of less than about 10 tically effective amount is equal to less than about 5x10 - 6 ng/ mL . mL - 1 In some embodiments Cmin and Cmar are averages over a In some embodiments , the Cmar divided by the therapeu plurality of treated individuals . tically effective amount is equal to less than about 1x10 - 25 In some embodiments , the average peak to trough ratio of mL - 1 . the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , In some embodiments , the Cmax divided by the therapeu 4 , 5 - tetrahydro - 1H - 3 - benzazepine in the individual is less tically effective amount is equal to less than about 5x10 - 7 than about 3 : 1 . mL - 1, In some embodiments , the average peak to trough ratio of In some embodiments , the plasma concentration of the 30 the plasma concentration of the ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 4 , 5 - tetrahydro - 1H - 3 -benzazepine in the individual is less zazepine in the individual has a AUCiast of at least about than about 2 : 1 . 1x10 - h ug /mL . In some embodiments, the average peak to trough ratio of In some embodiments , the plasma concentration of the the plasma concentration of the ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 35 4 , 5 - tetrahydro - 1H - 3 - benzazepine in the individual is less zazepine in the individual has a AUCiast of at least about than about 1 . 5 : 1 . 1x10 - 2 h -ug /mL . In some embodiments , the average peak to trough ratio of In some embodiments , the plasma concentration of the the plasma concentration of the ( R ) - 8 -chloro - 1 -methyl -2 , 3 , ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben 4 , 5 - tetrahydro - 1H - 3 - benzazepine in the individual is less zazepine in the individual has a AUCost of at least about 0 . 1 40 than about 1 . 1 : 1 . h .ug /mL . In any of the methods of the present invention , the peak In some embodiments , the plasma concentration of the to trough ratio of the plasma concentration of the ( R ) - 8 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine is an zazepine in the individual has a AUCiast of at least about 1 average over a plurality of treated individuals . h ug /mL . 45 In some embodiments, the Cmor occurs more than 30 In some embodiments , the plasma concentration of the minutes after the administering . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In some embodiments , the Cmor occurs more than 1 hour zazepine in the individual has a AUCjast of at least about 10 after the administering . max h ug /mL . In some embodiments , the mor occurs more than 2 hours In some embodiments , the plasma concentration of the 50 after the administering . ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben In any of the methods of the present invention , the Cmor zazepine in the individual has a AUCost of at least about 100 is an average over a plurality of treated individuals. h - ug/ mL . In some embodiments , the plurality of administrations is In any of the methods of the present invention , the at least about 30 . AUCiast is an average over a plurality of treated individuals . 55 In some embodiments , the plurality of administrations is In some embodiments , the AUCos divided by the thera - at least about 180 . peutically effective amount is equal to at least about 1x10 - 6 In some embodiments , the plurality of administrations is h /mL . at least about 365 . In some embodiments , the AUCtos divided by the thera - In some embodiments , the plurality of administrations is peutically effective amount is equal to at least about 1x10 - 5 60 at least about 730 . h /mL . In some embodiments , the method is more efficacious In some embodiments, the AUCos divided by the thera than an immediate - release method for weight management; peutically effective amount is equal to at least about 1x10 - 4 wherein the immediate -release method for weight manage h /mL . ment comprises administering to an individual in need In some embodiments , the AUCiast divided by the thera - 65 thereof, at the frequency, the plurality of administrations of peutically effective amount is equal to at least about 1x10 - 3 an immediate - release dosage form comprising the therapeu h /mL . tically effective dose of (R )- 8 -chloro - 1 -methyl - 2 ,3 , 4 ,5 - tet US 10 ,226 ,471 B2 47 48 rahydro - 1H - 3 -benzazepine or a pharmaceutically acceptable In some embodiments , the method for weight manage salt, solvate , or hydrate thereof. ment further comprises administering phentermine to the In some embodiments , the method is more efficacious individual. than an immediate - release method for weightmanagement ; One aspect of the present invention pertains to modified wherein the immediate -release method for weight manage - 5 release dosage forms of the present invention , for use in a ment comprises administering to an individual in need method of treatment of a disorder related to 5 -HT2c receptor thereof, an immediate - release dosage form comprising (R )- activity in an individual . 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine or One aspect of the present invention pertains to modified a pharmaceutically acceptable salt , solvate , or hydrate release dosage forms of the present invention , for use in a thereof; and wherein the AUC ; of ( R ) - 8 - chloro - 1 -methyl - 10 method of treatment of obesity in an individual. 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - benzazepine in the immediate - re - In some embodiments, the method for the treatment of lease method is equal to or greater than the AUClast of obesity further comprises the administration or prescription ( R ) -8 -chloro - 1 -methyl - 2 , 3 ,4 ,5 - tetrahydro - 1H -3 -ben of phentermine . zazepine in the method . 1 5 In some embodiments , the method for the treatment of In some embodiments , the weight management comprises obesity further comprises gastric electrical stimulation . weight loss . One aspect of the present invention pertains to modified In some embodiments , the weight management further release dosage forms of the present invention , for use in a comprises maintenance of weight loss . method for inducing weight loss , BMI loss , waist circum In some embodiments , the weight management further 20 ference loss or body fat percentage loss in an individual . comprises decreasing food consumption One aspect of the present invention pertains to modified In some embodiments , the weight management further release dosage forms of the present invention , for use in a comprises increasing meal- related satiety . method for inducing weight loss , BMI loss , waist circum In some embodiments , the weight management further ference loss or body fat percentage loss in an individual in comprises reducing pre -meal hunger. 25 preparation of the individual for bariatric surgery . In some embodiments , the weight management further One aspect of the present invention pertains to modified comprises reducing intra -meal food intake . rerelease dosage forms of the present invention , for use in a In some embodiments , the weight management further method for maintaining weight loss , BMI loss , waist cir comprises a reduced -calorie diet. cumference loss or body fat percentage loss in an individual . In some embodiments , the weight management further 3030 One aspect of the present invention pertains to modified comprises a program of regular exercise . release dosage forms of the present invention , for use in a In some embodiments , the weight management further method for maintaining weight loss, BMI loss , waist cir comprises both a reduced - calorie diet and a program of cumference loss or body fat percentage loss in an individual regular exercise . following bariatric surgery . In some embodiments , the individual in need of weight One aspect of the present invention pertains to modified management is an obese patient with an initial body mass release dosage forms of the present invention , for use in a index > 30 kg /m² . method for inducing satiety in an individual. In some embodiments , the individual in need of weight One aspect of the present invention pertains to modified management is an overweight patient with an initial body 40 release dosage forms of the present invention , for use in a mass index 227 kg/ m² in the presence of at least one weight method for decreasing food intake in an individual. related comorbid condition . One aspect of the present invention pertains to modified In some embodiments , the weight related co -morbid release dosage forms of the present invention , for use in a condition is selected from : hypertension , dyslipidemia , car - method for decreasing hunger in an individual. diovascular disease , glucose intolerance , and sleep apnea . 45 One aspect of the present invention pertains to modified In some embodiments , the individual in need of weight release dosage forms of the present invention , for use in a management has an initial body mass index 230 kg /m2 . method for decreasing food cravings in an individual. In some embodiments , the individual in need of weight One aspect of the present invention pertains to modified management has an initial body mass index 227 kg /m2 . release dosage forms of the present invention , for use in a In some embodiments , the individual in need of weight 50 method for increasing intermeal interval in an individual. management has an initial body mass index 227 kg/ m² in the One aspect of the present invention pertains to modified presence of at least one weight related comorbid condition . release dosage forms of the present invention , for use in a In some embodiments , the individual in need of weight method for the treatment of a disorder selected from : schizo management has an initial body mass index 227 kg /m² in the phrenia , anxiety , depression , psychoses, and alcohol addic presence of at least one weight related comorbid condition 55 tion in an individual. selected from : hypertension , dyslipidemia , cardiovascular In some embodiments , the disorder is schizophrenia . disease , glucose intolerance , and sleep apnea . In some embodiments , the disorder is anxiety . In some embodiments , the individual in need of weight In some embodiments , the disorder is depression . management has an initial body mass index 225 kg /m² . In some embodiments , the disorder is psychoses . In some embodiments , the individual in need of weight 60 In some embodiments , the disorder is alcohol addiction . management has an initial body mass index 225 kg /m2 in the In some embodiments , the modified -release dosage form presence of at least one weight related comorbid condition . comprises ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 In some embodiments , the individual in need of weight benzazepine hydrochloride or a pharmaceutically acceptable managementhas an initial body mass index 225 kg /m² in the solvate or hydrate thereof. presence of at least one weight related comorbid condition 65 In some embodiments , the modified -release dosage form selected from : hypertension , dyslipidemia , cardiovascular comprises ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 disease , glucose intolerance , and sleep apnea . benzazepine hydrochloride salt hemihydrate . US 10 , 226 , 471 B2 49 50 In some embodiments , the modified - release dosage form about 20 % microcrystalline cellulose; and about 0. 5 % mag comprises ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - nesium sterate ; and the coating comprises : about 85 % ethyl benzazepine hydrochloride salt hemihydrate , Form III . cellulose ; and about 15 % (hydroxypropyl ) methyl cellulose . In some embodiments , the modified -release dosage form In some embodiments , the modified - release dosage form further comprises an excipient selected from : (hydroxypro - 5 comprises a core tablet and a coating , wherein the weight to pyl) methyl cellulose , Kollidon SR , sodium carboxymethyl weight ratio of the core tablet to the coating is about 20 : 1 ; cellulose , Carbopol® , wax , and xanthan gum . and wherein the core tablet comprises : about 7 % ( R ) - 8 In some embodiments , the modified - release dosage form further comprises (hydroxypropyl ) methyl cellulose . chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine In some embodiments , the (hydroxypropyl ) methyl cellu - 10 hydrochloride salt hemihydrate , Form III ; about 22 . 5 % lose comprises Methocel® K4M . mannitol ; about 50 % (hydroxypropyl )methyl cellulose ; In some embodiments , the modified -release dosage form about 20 % microcrystalline cellulose ; and about 0 . 5 % mag further comprises one or more ingredients selected from : nesium sterate ; and the coating comprises : about 75 % ethyl microcrystalline cellulose , mannitol , and magnesium stear cellulose; and about 25 % (hydroxypropyl ) methyl cellulose . ate . 15 In some embodiments , the modified - release dosage form In some embodiments , the modified -release dosage form has a T80 % of at least 3 h . further comprises a film coating . In some embodiments , the modified -release dosage form In some embodiments , the film coating comprises has a 180 % of at least 6 h . Opadry® II Blue . In some embodiments , the modified -release dosage form In some embodiments , the film coating comprises ethyl 20 has a T80 % of at least 9 h . cellulose , Kollicoat® SR30D , Eudragit® , or cellulose In some embodiments , the modified - release dosage form acetate . has a T80 % of at least 12 h . In some embodiments , the film coating comprises ethyl In some embodiments , the modified - release dosage form cellulose . comprises a salt selected from : a pharmaceutically accept In some embodiments , the ethyl cellulose comprises 25 able salt of ( R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 Surelease® . benzazepine and pharmaceutically acceptable solvates and In some embodiments , the film coating further comprises hydrates thereof, and wherein the salt has an aqueous (hydroxypropyl ) methyl cellulose . solubility of less than about 200 mg /mL at about room In some embodiments , the (hydroxypropyl ) methyl cellu temperature . lose comprises Opadry® . 30 In some embodiments, the salt has an aqueous solubility In some embodiments , the ratio of the ethyl cellulose to of less than about 100 mg/ mL at about room temperature . the ( hydroxypropyl) methyl cellulose is about 75 : 25 . In some embodiments, the salt has an aqueous solubility In some embodiments, the ratio of the ethyl cellulose to of less than about 50 mg/mL at about room temperature . the (hydroxypropyl ) methyl cellulose is about 80 : 20 . In some embodiments , the salt has an aqueous solubility In some embodiments , the ratio of the ethyl cellulose to 35 of less than about 25 mg/mL at about room temperature . the (hydroxypropyl )methyl cellulose is about 85 : 15 . In some embodiments , the salt has an aqueous solubility In some embodiments, the modified -release dosage form of less than about 10 mg/ mL at about room temperature . comprises a core tablet and a coating ; wherein the core tablet I n some embodiments , the salt has an aqueous solubility comprises : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - of less than about 5 mg/mL at about room temperature . benzazepine hydrochloride salt hemihydrate , Form III ; man - 40 In some embodiments, the salt is selected from : ( R ) - 8 nitol; (hydroxypropyl )methyl cellulose ; microcrystalline chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine cellulose ; and magnesium sterate ; and the coating comprises hydroiodide salt , ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro Opadry® II Blue . 1H -3 -benzazepine maleate salt, (R ) -8 - chloro - 1- methyl - 2 , 3 , In some embodiments , the modified -release dosage form 4 , 5 -tetrahydro - 1H - 3 -benzazepine fumarate salt ; ( R ) -8 comprises a core tablet and a coating, wherein the weight to 45 chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine weight ratio of the core tablet to the coating is about 20 : 1 ; hemifumarate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra and wherein the core tablet comprises: about 7 % ( R ) - 8 - hydro - 1H - 3 - benzazepine orotate salt ; ( R ) - 8 -chloro - 1 chloro - 1 -methyl - 2, 3 ,4 ,5 - tetrahydro - 1H - 3 -benzazepine methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine orotate salt ; hydrochloride salt hemihydrate , Form III; about 22 . 5 % ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -ben mannitol ; about 50 % (hydroxypropyl ) methyl cellulose ; 50 zazepine di- 4 -acetamidobenzoate salt ; (R ) -8 -chloro - 1 about 20 % microcrystalline cellulose ; and about 0 . 5 % mag - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine trans- cinna nesium sterate ; and the coating comprises Opadry® II Blue. mate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 In some embodiments , the modified -release dosage form benzazepine heminapadisilate salt; (R )- 8 -chloro - 1- methyl comprises a core tablet and a coating ; wherein the core tablet 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( + ) -mandelate salt ; comprises: ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - 55 ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben benzazepine hydrochloride salt hemihydrate , Form III ;man - zazepine hemipamoate salt and pharmaceutically acceptable nitol; (hydroxypropyl ) methyl cellulose ; microcrystalline hydrates and solvates thereof. cellulose ; and magnesium sterate ; and the coating com - In some embodiments, the salt is selected from : ( R ) - 8 prises: ethyl cellulose; and (hydroxypropyl )methyl cellu - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine lose . 60 hydroiodide salt , ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro In some embodiments , the modified -release dosage form 1H -3 -benzazepine maleate salt, (R )- 8 -chloro - 1 -methyl -2 ,3 , comprises a core tablet and a coating , wherein the weight to 4 , 5 -tetrahydro - 1H - 3 - benzazepine fumarate salt ; ( R ) - 8 weight ratio of the core tablet to the coating is about 20 : 1 ; chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine and wherein the core tablet comprises: about 7 % ( R ) - 8 - hemifumarate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine 65 hydro - 1H - 3 -benzazepine orotate salt ; ( R ) - 8 - chloro - 1 hydrochloride salt hemihydrate , Form III ; about 22 . 5 % methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine trans - cinna mannitol ; about 50 % (hydroxypropyl ) methyl cellulose ; mate salt ; (R )- 8 - chloro - 1- methyl - 2 ,3 , 4, 5 - tetrahydro - 1H -3 US 10 ,226 ,471 B2 51 benzazepine heminapadisilate salt ; and pharmaceutically In some embodiments , the modified - release dosage form acceptable hydrates and solvates thereof. further comprises one or more pharmaceutically acceptable In some embodiments, the salt is selected from : (R ) - 8 excipients. chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine In some embodiments , the modified - release dosage form hydroiodide salt , ( R ) - 8 -chloro - 1 -methyl - 2 , 3 ,4 , 5 -tetrahydro - 5 is for oral administration to an individual. 1H - 3 -benzazepine maleate salt , ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , In some embodiments , the modified - release dosage form 4 , 5 -tetrahydro - 1H - 3 -benzazepine fumarate salt; ( R ) - 8 - is selected from the group consisting of: tablets , capsules, chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine pills , cachets, and lozenges. hemifumarate salt ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetra - In some embodiments , the modified - release dosage form hydro - 1H - 3 -benzazepine orotate salt ; ( R ) - 8 - chloro - 1 - 10 is a tablet. methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine orotate salt In some embodiments , the modified - release dosage form hydrate ; (R )- 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - is for administration in combination with phentermine. benzazepine di- 4 -acetamidobenzoate salt -cocrystal methyl One aspect of the present invention pertains to methods of ethyl ketone solvate ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetra - manufacturing a modified - release dosage form comprising : hydro - 1H - 3 -benzazepine trans - cinnamate salt ; ( R ) - 8 - 15 providing a compound selected from : ( R ) - 8 - chloro - 1 chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine methyl - 2 ,3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine , and pharma heminapadisilate salt; (R )- 8 -chloro - 1- methyl - 2 ,3 ,4 , 5 -tetra - ceutically acceptable salts , solvates , and hydrates thereof; hydro - 1H - 3 -benzazepine heminapadisilate salt solvate 1 ; and formulating the compound into a modified - release dos (R ) - 8 - chloro - 1 -methyl -2 , 3 ,4 ,5 - tetrahydro - 1H -3 -ben age form . zazepine heminapadisilate salt solvate 2 ; ( R ) - 8 - chloro - 1 - 20 In some embodiments , the method of manufacturing a methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( + ) -mandelate modified - release dosage form of the present invention com salt hydrate ; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - prises, for example , one or more of the following : dispersing 3 -benzazepine hemipamoate salt hydrate . a compound selected from : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 In some embodiments , the salt is selected from : ( R ) - 8 - tetrahydro - 1H - 3 -benzazepine , and pharmaceutically accept chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - benzazepine oro - 25 able solvates and hydrates thereof, in a rate - controlling tate salt hydrate ; ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - polymer matrix ; coating a tablet comprising a compound 1H - 3 -benzazepine di- 4 -acetamidobenzoate salt - cocrystal selected from : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 ,5 -tetrahydro methyl ethyl ketone solvate ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - 1H - 3 -benzazepine , and pharmaceutically acceptable sol tetrahydro - 1H - 3 - benzazepine heminapadisilate salt solvate vates and hydrates thereof, with a functional coating ; alter 1 ; (R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - ben - 30 nating layers comprising a compound selected from : ( R ) - 8 zazepine heminapadisilate salt solvate 2 ; ( R ) - 8 - chloro - 1 - chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine, and methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine ( + ) -mandelate pharmaceutically acceptable solvates and hydrates thereof, salt hydrate ; ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H with layers of functional coating; loading a bead with a 3 -benzazepine hemipamoate salt hydrate . compound selected from : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 In some embodiments , the salt is ( R )- 8 -chloro - 1 -methyl - 35 tetrahydro - 1H -3 -benzazepine , and pharmaceutically accept 2 , 3 ,4 , 5 - tetrahydro - 1H - 3 -benzazepine hydroiodide salt. able solvates and hydrates thereof; binding a compound In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl selected from : ( R ) - 8 -chloro - 1 - methyl- 2 , 3 , 4 , 5 - tetrahydro 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine maleate salt. 1H - 3 -benzazepine , and pharmaceutically acceptable sol In some embodiments , the salt is (R )- 8 -chloro - 1 -methyl vates and hydrates thereof, to a water - insoluble polymer 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - benzazepine fumarate salt . 40 resin ; and surrounding a reservoir comprising a compound In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - selected from : ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 -tetrahydro 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine hemifumarate salt . 1H - 3 -benzazepine , and pharmaceutically acceptable sol In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - vates and hydrates thereof , with a rate -controlling mem 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine orotate salt hydrate . brane . In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - 45 Any of the modified -release dosage forms of the present 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine orotate salt . invention can be further limited by any of the specific In some embodiments , the salt is (R )- 8 - chloro - 1- methyl - formulation characteristics anywhere in this application . 2 ,3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine orotate salt hydrate . Modified -Release Mechanisms In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - Drug release from a swellable hydrophilic matrix is a 2 ,3 , 4, 5 -tetrahydro - 1H - 3 -benzazepine di- 4 - acetamidobenzo - 50 complex phenomenon involving a number of physical pro ate salt- cocrystal methyl ethyl ketone solvate . cesses , such as water or biological fluid penetration into the In some embodiments , the salt is ( R )- 8 - chloro - 1 -methyl - matrix , polymer chain relaxation and disentanglement, 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine trans - cinnamate salt . matrix geometry variation , and polymer gel dissolution / In some embodiments , the salt is ( R ) - 8 -chloro - 1 -methyl - erosion (Hopfenberg H B , Hsu KC Swelling - controlled , 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - benzazepine heminapadisilate salt . 55 constant rate delivery systems Polym . Eng. Sci. 1978 ; In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - 18 ( 15 ) : 1186 - 1191; Lee P I Diffusional release of a solute 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine heminapadisilate salt from a polymeric matrix — approximate analytical solutions solvate 1 . J . Membrane Sci . 1980 ; 7 ( 3 ) : 255 - 275 ; Lee PI, Peppas N A In some embodiments , the salt is ( R ) - 8 - chloro - 1 -methyl - Prediction of polymer dissolution in swellable controlled 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 -benzazepine heminapadisilate salt 60 release systems J. Control. Release . 1987 ; 6 ( 1 ) :207 -215 ; solvate 2 . Harland R S , Gazzaniga A , Sangalli M E , Colombo P , In some embodiments , the salt is ( R ) - 8 -chloro - 1 -methyl - Peppas N A Drug/ polymer matrix swelling and dissolution 2 , 3, 4 , 5 -tetrahydro - 1H - 3 -benzazepine (+ ) -mandelate salt Pharm . Res. 1988 ; 5 (8 ) :488 -494 ). Upon exposure to an hydrate . aqueous solution or gastrointestinal fluids , the surface of a In some embodiments , the salt is ( R )- 8 -chloro - 1 -methyl - 65 tablet is wetted and the polymer hydrates form a gel layer 2 , 3 , 4 , 5 -tetrahydro - 1H - 3 - benzazepine hemipamoate salt around the matrix due to swelling . This gel layer slows down hydrate. water ingress into the tablet . Simultaneously , the drug inside US 10 , 226 , 471 B2 53 54 the gel layer dissolves and diffuses out. In case of a highly mechanism is non -Fickian or anomalous diffusion . If soluble drug , this usually leads to an initial burst release due n20 .89 , release is indicative of Case - II transport or com to the presence of drug on the surface of the matrix tablet . monly referred to as zero - order release. If n > 1 , release is The gel layer grows with time as water permeates continu considered to be super Case - Il transport . ously into the core of the matrix , thereby increasing the 5 Crystalline Forms thickness of the gel layer and providing a diffusion barrier to Polymorphism is the ability of a substance to exist as two drug release . When the periphery of the gel layer becomes or more crystalline phases that have different arrangements fully hydrated , the polymer chains become completely and /or conformations of the molecules in the crystal lattice . relaxed and can no longer maintain the integrity of the gel Polymorphs show the same properties in the liquid or layer , which leads to disentanglement and erosion of thehe 10 gaseous state but they may behave differently in the solid surface of the matrix . It is well established that concentration state . gradient- driven diffusion and polymer relaxation are the Besides single - component polymorphs, drugs can also most important rate - limiting steps in regulating drug release , exist as salts and other multicomponent crystalline phases . although the presence of drugs and additional excipients For example , solvates and hydrates may contain an active may enhance or suppress the swelling osmotic pressure at 15- pharmaceuticalP ingredient (API ) host and either solvent or the swelling front and thus modify the mechanical integrity water molecules, respectively , as guests . Analogously , when the guest compound is a solid at room temperature , the of polymer gel depending on the solubility of the additives. resulting form is often called a cocrystal. Salts , solvates , Essentially, diffusion and polymer relaxation compete in hydrates , and cocrystals may show polymorphism as well . controlling drug release , leading to the usually observed“ 20 Crystalline phases that share the same API host , but differ non - Fickian release kinetics . with respect to their guests , may be referred to as pseudo Over the past few decades , great efforts have been made polymorphs of one another. in attempts to generalize the swelling and dissolution of Solvates contain molecules of the solvent of crystalliza polymers in general, and to quantify the drug - release process tion in a definite crystal lattice . Solvates, in which the from the swellable hydrophilic matrices in particular (Fan L .25 solvent of crystallization is water , are termed hydrates . T , Singh S K Controlled release , a quantitative treatment Because water is a constituent of the atmosphere , hydrates New York , N . Y .: Springer - Verlag , 1989; Siepmann J , Peppas of drugs may be formed rather easily . Recently , polymorph N A Modeling of drug release from delivery systems based screens of 245 compounds revealed that about 90 % of them on hydroxypropyl methylcellulose (HPMC ) Adv . Drug Deliv . exhibited multiple solid forms. Overall, approximately half Rev. 2001 ; 48 (2 - 3 ): 139 - 157 ; Costa P , Lobo JMS Modeling 30 the compounds were polymorphic , often having one to three and comparison of dissolution profiles Eur. J . Pharm . Sci . forms. About one -third of the compounds formed hydrates, 2001; 13 ( 2 ) : 123 - 133 ) . Because of the synchronous occur and about one - third formed solvates . Data from cocrystal rence of numerous phenomena during dissolution of a screens of 64 compounds showed that 60 % formed cocrys swellable hydrophilic matrix , the developed mathematical tals other than hydrates or solvates. ( G . P . Stahly, Crystal models are rather sophisticated , and in most cases have to be 35 Growth & Design ( 2007 ) , 7 ( 6 ) , 1007 - 1026 . ) solved by numerical algorithms or finite element methods, The present invention is directed , inter alia , to crystalline which limits the routine application of those models (Paul D forms of salts of ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro R , McSpadden S K Diffusional release of a solute from a 1H - 3 -benzazepine and hydrates and solvates thereof. The polymeric matrix J. Membrane Sci . 1976 ; 1 : 33 - 48 ; Tu YO crystalline forms of the present invention can be identified A multi -phase Stefan problem describing the swelling and7. 40 by unique solid state signatures with respect to , for example , the dissolution of glassy polymer Quar. Appl. Math . 1977 ; differential scanning calorimetry (DSC ), X -ray powder dif XXXV: 269 - 285 ; Siepmann J , Streubel A , Peppas N A fraction (PXRD ) , and other solid state methods. Further Understanding and predicting drug delivery from hydro characterization with respect to water or solvent content of philic matrix tablets using the " sequential layer " model the crystalline forms of the present invention can be gauged Pharm . Res. 2002 ; 19 ( 3 ): 306 - 314 ). Equation 1 is one of the 45 by any of the following methods for example , thermogra most widely used equations in modeling drug release from vimetric analysis ( TGA ) , DSC and the like . For DSC , it is a swellable hydrophilic matrix : known that the temperatures observed will depend upon sample purity , the rate of temperature change , as well as M . Equation 1 sample preparation technique and the particular instrument - = k . 50 employed . Thus, the values reported herein relating to DSC M . thermograms can vary by about 16° C . The values reported herein relating to DSC thermograms can also vary by about wherein M , is the amount of drug released at time t , M ., is 20 joules per gram . For PXRD , the relative intensities of the total drug loading , and M / M , is the fraction of drug the peaks can vary , depending upon the sample preparation released at time t (Korsmeyer RW , Gurny R , Doelker E , 55 technique, the sample mounting procedure and the particular Buri P , Peppas N A Mechanisms of solute release from instrument employed . Moreover, instrument variation and porous hydrophilic polymers. Int. J. Pharm . 1983 ; 15 ( 1 ): 25 - other factors can often affect the 20 values . Therefore , the 35 ; Ritger PL , Peppas NAA simple equation for description peak assignments of diffraction patterns can vary by about of solute release 1 . Fickian and non - fickian release from 10 .2° 20 . The relative intensities of the reported peaks can non - swellable devices in the form of slabs , spheres, cylin - 60 also vary . For TGA , the features reported herein can vary by ders or discs J . Control. Release . 1987 ; 5 ( 1 ) :23 - 36 ) . In about + 5° C . The TGA features reported herein can also vary Equation 1 , k is a constant incorporating the structural and by about 2 % weight change due to , for example, sample geometric characteristic of a matrix system , and n is an variation . Further characterization with respect to hygro exponent that characterizes the release mechanism . Gener - scopicity of the crystalline form can be gauged by , for ally , this equation is only applicable for M / M . 580 % . In the 65 example , dynamic moisture sorption (DMS ) . The DMS case of cylindrical matrix tablets , the drug - release mecha - features reported herein can vary by about + 5 % relative nism is Fickian diffusion if n = 0 .45 . If 0 .45 < n < 0 .89 , the humidity . The DMS features reported herein can also vary US 10 ,226 ,471 B2 55 56 by about 25 % weight change . The deliquescence relative TABLE 2 - continued humidity (DRH ) measurements by water activity meter are sensitive to sample quality and quantity . The DRH measure Pos . ments reported herein can vary by about + 5 % RH . (°20 ) Compound 1 Hydrochloride Salt Hemihydrate 33 . 3 The physical properties of Form III of Compound 1 33 . 8 hydrochloride salt hemihydrate are summarized in Table 1 35 . 8 below . Form III of Compound 1 hydrochloride salt hemihydrate 10 can be prepared as described in Example 4 . TABLE 1 Compound 1 Hydroiodide Salt Compound 1 Hydrochloride Salt Hemihydrate, Form III One aspect of the present invention pertains to a crystal PXRD FIG . 1 : Peaks at 13. 7° , 14 . 99 , 15 .4° , 15 .8° , 16 . 7°, 18 . 9° 20 line form of (R ) - 8 -chloro - 1 -methyl - 2, 3, 4 ,5 - tetrahydro - 1H DSC FIG . 2 : 95° C . ( dehydration ) ; 200° C . (melt ) 3 - benzazepine hydroiodide salt (Compound 1 hydroiodide TGA FIG . 3 : 3 . 7 % water loss 15 salt ). In some embodiments , the crystalline form of ( R )- 8 DMS FIG . 4 : non -hygroscopic chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -benzazepine hydroiodide salt is Form I ( Compound 1 hydroiodide salt , Compound 1 hydrochloride salt hemihydrate , Form III Form I) . The physical properties of Form I of Compound 1 displays a dehydration feature calculated as a 3 . 7 % weight hydroiodide salt are summarized in Table 3 below . loss which is consistent with the theoretical weight loss of 3 .7 % for a hemihydrate . Analysis by DSC further confirms TABLE 3 the TGA results , where Compound 1 hydrochloride salt Compound 1 Hydroiodide Salt, Form I hemihydrate , Form III shows a dehydration event at about FIG . 5 : Peaks of 30 % relative intensity at 13 . 32 , 15 . 35 95° C . and a melting /decomposition endotherm at about 3 PXRD < 17 . 19 , 18 .46 , 19 .62 , 23 .07 , 23 . 73 , 26 . 70 , 28. 91 , 29 . 37 , 29 .70 , 200 - 201° C . and 29 . 87° 20 DMS data shows that Compound 1 hydrochloride salt TGA FIG . 6 : anhydrous with significant weight loss after melting hemihydrate , Form III is substantially non - hygroscopic , DSC FIG . 6 : extrapolated onset temperature about 121° C . ; adsorbing less than 0 . 5 wt % water out to and including the enthalpy of fusion 88 J/ g 90 % RH hold at 25° C . and the XRPD pattern showed no z DMS FIG . 7 : non -hygroscopic change in crystalline form after the DMS cycle . 30 Certain X - ray powder diffraction peaks for Compound 1 The TGA showed Compound 1 hydroiodide salt to be hydrochloride salt hemihydrate , Form III are shown in Table anhydrous, which was confirmed by Karl Fischer analysis . 2 below . Melting onset by DSC was 121° C . ; melting was accompa nied by the beginning of large weight loss ( > 30 % ) out to TABLE 2 about 200° C . DMS analysis showed that the title salt was non -hygro Pos . scopic. Based on water activity measurement of a saturated ( 20 ) aqueous solution with excess solid , the DRH was 99 % RH 10 . 2 at 25° C . Certain X - ray powder diffraction peaks for Form 12 . 7 41 13 .7 I of Compound 1 hydroiodide salt are shown in Table 4 14 . 9 below . 15 . 4 15 . 8 TABLE 4 16 . 7 18 . 5 Pos. ( 20 ) Rel . Int. ( % ) 18 . 9 19 . 2 7 .69 5 . 14 20 . 1 13 . 32 49 . 45 25 . 3 14 .88 21 .72 25 . 7 15 . 35 30 . 89 26 . 0 17 . 19 92 .91 26 . 5 18 . 05 24 . 11 26 . 9 18 .46 94 .03 27 . 6 19 .62 94 . 85 28 . 2 19 . 96 17. 75 20 . 5 21 . 42 12 . 98 21 . 4 23 .07 62 . 26 22 . 8 23 . 73 100 . 00 23 . 2 25 .60 4 . 89 23. 5 25 . 90 8 .24 24 . 0 26 . 40 26 .59 24 . 2 26 . 70 89 .53 24 . 7 28 . 13 19 . 48 29 . 0 28 .67 15 . 75 30 . 0 28 . 91 89 .32 30 . 3 29 . 37 35 .62 30 . 8 29 . 70 31 . 97 31 . 1 29 . 87 36 .93 32 . 0 30 . 93 16 .46 32 . 3 32. 11 7. 39 32 . 7 32 .60 11 . 00 US 10 ,226 ,471 B2 57 58 TABLE 4 -continued is meant that the reported DMS features can vary by about + 5 % relative humidity and by about 5 % weight change . Pos . ( 20 ) Rel. Int. ( % ) Form I of Compound 1 hydroiodide salt can be prepared 34 .65 23 . 37 by any of the suitable procedures known in the art for 35 . 92 11 .58 5 preparing crystalline polymorphs . In some embodiments 36 .43 7 . 12 Form I of Compound 1 hydroiodide salt can be prepared as 36 .65 7 . 39 37 . 17 23 . 25 described in Example 3 . 1 . In some embodiments , Form I of 38 . 30 2 .88 Compound 1 hydroiodide salt can be prepared by slurrying 38 . 85 11 . 23 crystalline Compound 1 hydroiodide salt containing one or 39 .66 19 . 10 10 more crystalline forms other than Form I. In some embodi ments , the crystalline form of Compound 1 hydroiodide salt One aspect of the present invention is directed to a can be prepared by recrystallizing crystalline Compound 1 crystalline form of Compound 1 hydroiodide salt having an hydroiodide salt containing one or more crystalline forms X -ray powder diffraction pattern comprising a peak , in terms other than Form I. talline 15 Compound 1 Maleate Salt of 20 , at about 23 .73° . In some embodiments , the crystalline One aspect of the present invention pertains to a crystal form has an X - ray powder diffraction pattern comprising a line form of ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H peak , in terms of 20 , at about 19. 62º . In some embodiments , 3 -benzazepine maleate salt ( Compound 1 maleate salt ). In the crystalline form has an X - ray powder diffraction pattern some embodiments, the crystalline form of ( R ) - 8 -chloro - 1 comprising peaks, in terms of 20 , at about 23 . 73° and about 2030 methyl- 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine maleate salt is 19 .62º . In some embodiments, the crystalline form has an Form I (Compound 1 maleate salt , Form I ). The physical X - ray powder diffraction pattern comprising peaks , in terms properties of Form I of Compound 1 maleate salt are of 20 , at about 23 . 73° and about 18 .46° . In some embodi ments , the crystalline form has an X - ray powder diffraction summarized in Table 5 below . pattern comprising peaks, in terms of 20 , at about 23 .73° , 25 TABLE 5 about 19 .62º and about 18 .46° . In some embodiments, the crystalline form has an X - ray powder diffraction pattern Compound 1 Maleate Salt, Form I comprising peaks , in terms of 20 , at about 23 . 73°, about PXRD FIG . 8 : Peaks of 26 % relative intensity at 11 . 93 , 15 .07 , 19. 62° , about 18 .46° , about 17 . 19°, about 26 .70° , about 16 .23 , 17 .95 , 19 . 32 , 22 . 04 , 23 . 88 , 24 .46 , 26 . 31 , 26 .58 , 27 .07 , and 28 . 29° 20 28 . 91° , and about 23 .07º . In some embodiments , the crys - 30 TGA FIG . 9 : < 0 . 2 % weight loss up to about 150° C . talline form has an X - ray powder diffraction pattern com DSC FIG . 9 : extrapolated onset temperature about 166° C . ; prising peaks, in terms of 20 , at about 23. 73° , about 19 .62° , enthalpy of fusion 81 J / g about 18 .46° , about 17 . 19° , about 26 . 70° , about 28 . 91°, DMS FIG . 10 : 0 . 15 % weight gain at 90 % RH about 23 . 07° , about 13 . 32° , about 29 .87° , and about 29 . 37º. One aspect of the present invention is directed to a crystal - Form I of Compound 1 maleate salt had a melting onset line form of Compound 1 hydroiodide salt having an X - ray temperature about 166° C . The TGA was consistent with an powder diffraction pattern comprising one or more peaks anhydrous salt. It was not hygroscopic , picking up just listed in Table 4 . In some embodiments , the crystalline form 0 . 15 % weight out to and including the 90 % RH hold at 25° has an X - ray powder diffraction pattern substantially as 10 C . shown in FIG . 5 , wherein by “ substantially ” is meant that the Certain X - ray powder diffraction peaks for Form I of reported peaks can vary by about + 0 . 2° 20 , and also that the Compound 1 maleate salt are shown in Table 6 below . relative intensities of the reported peaks can vary . In some embodiments , the crystalline form of Compound TABLE 6 1 hydroiodide salt has a differential scanning calorimetry 45 thermogram comprising an endotherm with an extrapolated Pos. ( 20 ) Rel . Int. ( % ) onset temperature between about 105º C . and about 135º C . 6 . 27 1 . 11 9 . 75 0 . 37 In some embodiments , the crystalline form of Compound 1 11 . 93 100 . 00 hydroiodide salt has a differential scanning calorimetry 13 . 10 5 . 17 thermogram comprising an endotherm with an extrapolated 50 14 .08 0 . 80 onset temperature at about 121° C . In some embodiments , 15 . 07 11 . 71 15 .87 3 . 43 the crystalline form of Compound 1 hydroiodide salt has a 16 . 23 10 .63 differential scanning calorimetry thermogram comprising an 17 .56 5 . 14 endotherm with an associated heat flow of about 88 joules 17 . 95 7 .04 per gram . In some embodiments , the crystalline form of 55 18 .23 2 . 16 18 . 70 4 .99 Compound 1 hydroiodide salt has a thermogravimetric 19 . 32 13 . 61 analysis profile substantially as shown in FIG . 6 , wherein by 20 .08 1 .21 “ substantially ” is meant that the reported TGA features can 20 . 68 5 .64 vary by about + 5° C . and by about + 2 % weight change . 21 . 16 3 . 12 22 . 04 7 . 58 In some embodiments , the crystalline form of Compound 60 22 .66 5 .78 1 hydroiodide salt has a differential scanning calorimetry 22 . 86 4 .49 thermogram substantially as shown in FIG . 6 , wherein by 23 . 88 49 .41 24 . 46 23. 70 “ substantially ” is meant that the reported DSC features can 25 . 14 3 .79 vary by about + 6° C . and by about + 20 joules per gram . 25 .69 4 .62 In some embodiments , the crystalline form of Compound 65 26 . 31 27 . 36 1 hydroiodide salt has a dynamic moisture sorption profile 26 .58 9 . 01 substantially as shown in FIG . 7 , wherein by “ substantially ” US 10 ,226 ,471 B2 59 60 TABLE 6 - continued stantially ” is meant that the reported TGA features can vary by about 25° C . and by about + 2 % weight change . Pos . ( 20 ) Rel. Int. ( % ) In some embodiments , the crystalline form of Compound 27 . 07 6 . 57 1 maleate salt has a differential scanning calorimetry ther 27 .61 3 . 09 mogram substantially as shown in FIG . 9 , wherein by 28 . 29 6 . 17 " substantially ” is meant that the reported DSC features can 29 . 06 1 . 62 30 .00 2 . 08 vary by about + 6° C . and by about + 20 joules per gram . 30 . 40 1 . 34 In some embodiments , the crystalline form of Compound 30 . 93 1 . 95 1 maleate salt has a dynamic moisture sorption profile 31 . 40 1. 55 10 substantially as shown in FIG . 10 , wherein by " substan 31. 90 5 . 47 32 .60 1 . 53 tially ” is meant that the reported DMS features can vary by 33 .03 2 .00 about + 5 % relative humidity and by about + 5 % weight 33 .63 1. 35 change . 34. 32 0 . 98 Form I of Compound 1 maleate salt can be prepared by 35 . 02 0 .94 15 any of the suitable procedures known in the art for preparing 36 . 22 3 .42 36 .42 2 . 93 crystalline polymorphs . In some embodiments Form I of 36 . 84 4 . 04 Compound 1 maleate salt can be prepared as described in 37. 43 1 . 23 Example 3 . 2 . In some embodiments, Form I of Compound 37 . 90 2 . 36 1 maleate salt can be prepared by slurrying crystalline 38 . 31 2 . 07 38 .88 0 . 70 20 Compound 1 maleate salt containing one or more crystalline forms other than Form I . In some embodiments , the crys talline form of Compound 1 maleate salt can be prepared by One aspect of the present invention is directed to a recrystallizing crystalline Compound 1 maleate salt contain crystalline form of Compound 1 maleate salt having an ing one or more crystalline forms other than Form I . X - ray powder diffraction pattern comprising a peak , in terms 25 Compound 1 Fumarate Salt of 20 , at about 11 .93° . In some embodiments , the crystalline One aspect of the present invention pertains to a crystal form has an X - ray powder diffraction pattern comprising a line form of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H peak , in terms of 20 , at about 23 .88° . In some embodiments , 3 -benzazepine fumarate salt (Compound 1 fumarate salt ) . In the crystalline form has an X - ray powder diffraction pattern some embodiments, the crystalline form of ( R ) - 8 - chloro - 1 comprising peaks, in terms of 20 , at about 11. 930 and about 30 methyl- 2 ,3 , 4 ,5 - tetrahydro - 1H -3 -benzazepine fumarate salt 23 .88° . In some embodiments , the crystalline form has an is Form I (Compound 1 fumarate salt , Form I ) . The physical X - ray powder diffraction pattern comprising peaks, in terms properties of Form I of Compound 1 fumarate salt are of 20 , at about 11. 93° and about 26 .31° . In some embodi summarized in Table 7 below . ments, the crystalline form has an X - ray powder diffraction pattern comprising peaks, in terms of 20 , at about 11 . 93°, 35 TABLE 7 about 23 . 88°, and about 26 . 31°. In some embodiments , the Compound 1 Fumarate Salt, Form I crystalline form has an X - ray powder diffraction pattern PXRD FIG . 11 : Peaks of 10 % relative intensity at 11. 59 , 13 .08 , comprising peaks, in terms of 20 , at about 11. 93° , about 17 . 11 , 17. 99 , 18 . 36 , 19 .82 , 23 .21 , 23 .67 , 25 .40 , 25 . 50 , 23 .88° , about 26 .31° , about 24 . 46°, about 19 .32° , about 25 .89 , 26 .98 , 27. 36 , and 28 .78° 20 15 .07° , and about 16 .23° . In some embodiments , the crys - TGA FIG . 12 : No significant weight loss up to about 150° C .; talline form has an X - ray powder diffraction pattern com 16 . 85 % weight between about 147° C . and about 210° C . , prior to the melt onset prising peaks , in terms of 20 , at about 11. 930, about 23 . 88° , DSC FIG . 12 : extrapolated onset temperature about 219° C . about 26 .31° , about 24 .46° , about 19 .32° , about 15 .07º , DMS FIG . 13 : non - hygroscopic up to 90 % RH about 16 .23° , about 26 .58° , about 22 .04° , and about 17 . 950. 45 One aspect of the present invention is directed to a crystal Compound 1 fumarate salt, Form I showed a very high line form of Compound 1 maleate salt having an X - ray melting onset of 218 - 2190 ? depending on the s powder diffraction pattern comprising one or more peaks analyzed . TGA showed the salt to be anhydrous, with listed in Table 6 . In some embodiments , the crystalline form significant weight loss prior to the melting onset, likely due has an X -ray powder diffraction pattern substantially as 50 to vaporization of the salt of components thereof. Com shown in FIG . 8 , wherein by “ substantially ” is meant that the pound 1 fumarate salt , Form I was non - hygroscopic by DMS reported peaks can vary by about + 0 .2° 20 , and also that the analysis out to and including the 90 % RH hold at 25° C . and relative intensities of the reported peaks can vary . the DRH by water activity meter was 99 % RH at 25° C . In some embodiments , the crystalline form of Compound Certain X - ray powder diffraction peaks for Form I of 1 maleate salt has a differential scanning calorimetry ther - 55 Compound 1 fumarate salt are shown in Table 8 below . mogram comprising an endotherm with an extrapolated onset temperature between about 150° C . and about 180° C . TABLE 8 In some embodiments , the crystalline form of Compound 1 maleate salt has a differential scanning calorimetry thermo Pos. (°20 ) Rel. Int. ( % ) gram comprising an endotherm with an extrapolated onset 60 5 . 21 1 . 52 temperature at about 166° C . In some embodiments , the 6 .54 8 .43 crystalline form of Compound 1 maleate salt has a differ 11 . 59 12 . 41 ential scanning calorimetry thermogram comprising an 13 . 08 100 .00 14 .83 6 .90 endotherm with an associated heat flow of about 81 joules 15 . 82 2 . 85 per gram . In some embodiments , the crystalline form of 65 16 . 10 1 . 59 Compound 1 maleate salt has a thermogravimetric analysis 17 . 11 16 . 74 profile substantially as shown in FIG . 9 , wherein by “ sub US 10 ,226 ,471 B2 61 62 TABLE 8 -continued onset temperature between about 205º C . and about 235° C . In some embodiments , the crystalline form of Compound 1 Pos . (© 20 ) Rel. Int. ( % ) fumarate salt has a differential scanning calorimetry ther 17 . 99 37 . 47 mogram comprising an endotherm with an extrapolated 18 . 36 17 . 64 onset temperature at about 219° C . In some embodiments , 19 . 34 2 .94 19 . 82 21. 63 the crystalline form of Compound 1 fumarate salt has a 20 .49 9 . 18 thermogravimetric analysis profile substantially as shown in 20 . 89 9 . 65 FIG . 12 , wherein by “ substantially ” is meant that the 21 . 18 9 .82 reported TGA features can vary by about + 5° C . and by 21 . 50 7 .76 10 22 .28 4 .79 about + 2 % weight change . 23 . 21 15 . 98 In some embodiments , the crystalline form of Compound 23 .67 13. 08 1 fumarate salt has a differential scanning calorimetry ther 25 .40 15 . 12 25 . 50 18 .21 mogram substantially as shown in FIG . 12 , wherein by 25. 89 18 . 50 15 " substantially ” is meant that the reported DSC features can 26 .50 8 . 01 vary by about + 6° C . and by about + 20 joules per gram . 26 . 98 18 .69 27 . 36 16 . 46 In some embodiments , the crystalline form of Compound 27 . 86 6 . 57 1 fumarate salt has a dynamic moisture sorption profile 28 . 36 4 . 33 substantially as shown in FIG . 13 , wherein by " substan 28 . 78 10 .03 29 .03 6 .71 20 tially ” is meant that the reported DMS features can vary by 29 . 56 2 . 87 about 15 % relative humidity and by about 25 % weight 29 . 91 1 .62 change . 30 .49 1 . 74 31 . 14 2 . 15 Form I of Compound 1 fumarate salt can be prepared by 31 .61 2 . 14 any of the suitable procedures known in the art for preparing 31 . 86 1 .78 25 crystalline polymorphs . In some embodiments Form I of 33 . 06 5 . 03 34 . 06 2 . 59 Compound 1 fumarate salt can be prepared as described in 34 . 50 2 . 02 Example 3 . 3 . In some embodiments , Form I of Compound 36 . 24 1 .65 1 fumarate salt can be prepared by slurrying crystalline 36 .64 0 . 86 Compound 1 fumarate salt containing one or more crystal 37 .09 1 . 36 37 .64 1 . 82 line forms other than Form I. In some embodiments , the 38 .24 1 .51 crystalline form of Compound 1 fumarate salt can be pre 39 . 40 1 . 38 pared by recrystallizing crystalline Compound 1 fumarate salt containing one or more crystalline forms other than One aspect of the present invention is directed to a 35 Form I. crystalline form of Compound 1 fumarate salt having an Compound 1 Hemifumarate Salt X - ray powder diffraction pattern comprising a peak , in terms One aspect of the present invention pertains to a crystal of 20 , at about 13 .08° . In some embodiments , the crystalline line form of (R )- 8 -chloro - 1 -methyl - 2 , 3, 4 ,5 - tetrahydro - 1H form has an X - ray powder diffraction pattern comprising a 3 -benzazepine hemifumarate salt (Compound 1 hemifumar peak , in terms of 20 , at about 17 .99º . In some embodiments , 40 aate salt) . In some embodiments , the crystalline form of the crystalline form has an X - ray powder diffraction pattern ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 -ben comprising peaks , in terms of 20 , at about 13 . 08° and about zazepine hemifumarate salt is Form I ( Compound 1 hemi 17 . 990 . In some embodiments , the crystalline form has an fumarate salt , Form I) . The physical properties of Form I of X - ray powder diffraction pattern comprising peaks, in terms Compound 1 hemifumarate salt are summarized in Table 9 of 20 , at about 13. 08° and about 19. 82º . In some embodi- 45 DE ments , the crystalline form has an X - ray powder diffraction pattern comprising peaks, in terms of 20 , at about 13 .08° , TABLE 9 about 17 .999 , and about 19. 82º . In some embodiments , the Compound 1 Hemifumarate Salt , Form I crystalline form has an X -ray powder diffraction pattern comprising peaks, in terms of 20 , at about 13 .08° , about 50 PXRD FIG . 14 : Peaks of 10 % relative intensity at 11. 21, 13. 12 , 14 . 41, 14 .60 , 18 . 00 , 19 .85 , 20 . 54 , 21 .47 , 22 . 15 , 23 . 24 , 17 . 999 , about 19 . 82° , about 26 . 98° , about 25 .899 , about 25 . 34 , 25 .57 , 25 .98 , and 27 .60° 20 25. 50°, and about 18 . 36º. In some embodiments , the crys TGA FIG . 15 : about 27 % weight loss up to about 160° C . talline form has an X -ray powder diffraction pattern com DSC FIG . 15 : extrapolated onset temperature about 158° C . ; prising peaks , in terms of 20 , at about 13 . 08° , about 17 . 999, enthalpy of fusion 51 J / g about 19 . 82°, about 26 . 98°, about 25. 89° , about 25 .50° , 55 DMSDN FIG . 16 : ~ 8 % weight gain at about 50 % RH about 18 . 36° , about 17 . 11°, about 27 . 36° , and about 23 .21° . One aspect of the present invention is directed to a crystal Compound 1 hemifumarate salt, Form I had a melting line form of Compound 1 fumarate salt having an X - ray onset of 158° C . by DSC , however, significant weight loss powder diffraction pattern comprising one or more peaks occurred prior to this melting onset based on TGA data . The listed in Table 8 . In some embodiments , the crystalline form 60 weight loss was slightly more than the theoretical amount of has an X - ray powder diffraction pattern substantially as fumaric acid for an anhydrous hemifumarate salt ( 27 . 0 % vs . shown in FIG . 11 , wherein by “ substantially ” is meant that 22 . 9 % ) . the reported peaks can vary by about + 0 . 2° 20 , and also that Compound 1 hemifumarate salt , Form I formed a hydrate the relative intensities of the reported peaks can vary . during DMS analysis , which was labile enough to lose the In some embodiments , the crystalline form of Compound 65 water upon desorption to 5 % RH at 25° C . The ~ 8 % weight 1 fumarate salt has a differential scanning calorimetry ther - gain is slightly higher than the theoretical % weight gain mogram comprising an endotherm with an extrapolated (7 .1 % ) for a monohydrate . US 10 , 226 , 471 B2 63 64 Certain X - ray powder diffraction peaks for Form I of can vary by about 10 .2° 20 , and also that the relative Compound 1 hemifumarate salt are shown in Table 10 intensities of the reported peaks can vary . below . In some embodiments , the crystalline form of Compound 1 hemifumarate salt has a differential scanning calorimetry TABLE 10 5 thermogram comprising an endotherm with an extrapolated onset temperature between about 140° C . and about 170° C . Pos. (020 ) Rel . Int. ( % ) In some embodiments , the crystalline form of Compound 1 5 .22 7 .76 hemifumarate salt has a differential scanning calorimetry 11 . 21 68 . 97 thermogram comprising an endotherm with an extrapolated 11 .62 6 . 75 10 13 . 12 14 . 50 onset temperature at about 158° C . In some embodiments , 14 . 41 18 .42 the crystalline form of Compound 1 hemifumarate salt has 14 .60 16 . 63 a differential scanning calorimetry thermogram comprising 15 . 53 8 .04 17 . 17 7 .72 an endotherm with an associated heat flow of about 51 joules 18 . 00 44 . 75 per gram . In some embodiments , the crystalline form of 18 . 45 7 . 42 Compound 1 hemifumarate salt has a thermogravimetric 19 . 85 13 .99 20 . 54 100 . 00 analysis profile substantially as shown in FIG . 15 , wherein 21 . 47 12 . 45 by “ substantially ” is meant that the reported TGA features 22 . 15 20 . 83 can vary by about + 5° C . and by about + 2 % weight change. 23 . 24 12 . 38 23 . 82 6 .64 In some embodiments , the crystalline form of Compound 24 . 26 2 . 82 1 hemifumarate salt has a differential scanning calorimetry 24 .92 6 .64 thermogram substantially as shown in FIG . 15 , wherein by 25 .34 11. 01 “ substantially ” is meant that the reported DSC features can 25. 57 14 . 60 25 . 98 24 . 15 vary by about +6° C . and by about 120 joules per gram . 27 .02 4 . 46 25 In some embodiments , the crystalline form of Compound 27 .60 10 .77 1 hemifumarate salt has a dynamic moisture sorption profile 28 . 55 6 .21 substantially as shown in FIG . 16 , wherein by “ substan 28 .92 6 . 45 30 . 41 5 .52 tially ” is meant that the reported DMS features can vary by 31 . 75 9 . 94 about 25 % relative humidity and by about 15 % weight 32 . 34 3 .42 30 change. 33 . 06 2 . 05 Form I of Compound 1 hemifumarate salt can be prepared 33 . 58 4 . 55 34 .82 6 . 53 by any of the suitable procedures known in the art for 35 .67 2 .88 preparing crystalline polymorphs . In some embodiments 36 .77 1 .82 Form I of Compound 1 hemifumarate salt can be prepared 37 .51 3 .33 35 as described in Example 3. 4 . In some embodiments , Form I 38 . 46 1 .55 of Compound 1 hemifumarate salt can be prepared by slurrying crystalline Compound 1 hemifumarate salt con One aspect of the present invention is directed to a taining one or more crystalline forms other than Form I . In crystalline form of Compound 1 hemifumarate salt having some embodiments, the crystalline form of Compound 1 an X - ray powder diffraction pattern comprising a peak , in 40 hemifumarate salt can be prepared by recrystallizing crys talline Compound 1 hemifumarate salt containing one or terms of 20 , at about 20 . 54° . In some embodiments , the more crystalline forms other than Form I . crystalline form has an X - ray powder diffraction pattern Compound 1 Orotate Salt comprising a peak , in termsof 20 , at about 11 .21° . In some One aspect of the present invention pertains to a crystal embodiments , the crystalline form has an X - ray powder 45 line form of ( R )- 8 -chloro - 1 -methyl - 2, 3 ,4 , 5 -tetrahydro - 1H diffraction pattern comprising peaks , in terms of 20 , at about 43 3 -benzazepine orotate salt (Compound 1 orotate salt ) . In 20 .54º and about 11. 21° . In some embodiments , the crys some embodiments, the crystalline form of ( R ) - 8 - chloro - 1 talline form has an X - ray powder diffraction pattern com methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine orotate salt is prising peaks, in terms of 20 , at about 20 .54º and about Form I (Compound 1 orotate salt, Form I ) . The physical 18 . 00°. In some embodiments , the crystalline form has an 50 properties of Form I of Compound 1 orotate salt are sum X - ray powder diffraction pattern comprising peaks, in terms marized in Table 11 below . of 20 , at about 20 .54° , about 11 .21° , and about 18 .00° . In some embodiments, the crystalline form has an X - ray pow TABLE 11 der diffraction pattern comprising peaks , in terms of 20 , at about 20 .54° , about 11 .21° , about 18 . 00°, about 25 . 98°, 55 Compound 1 Orotate Salt, Form I about 22 . 15º, about 14 .41° , and about 14 .60° . In some PXRD FIG . 17 : Peaks of 20 % relative intensity at 6 . 30 , 12 . 44 , embodiments , the crystalline form has an X -ray powder 14 .59 , 14 .86 , 16 . 96 , 19 .62 , 19. 71 , 24 .07 , 24 .55 , 25 .02 , 26 .64 , and 28. 64 920 diffraction pattern comprising peaks, in terms of 20 , at about TGA FIG . 18 : no significant weight loss up to about 200° C . 20 .54 ' , about 11 . 21°, about 18 .00° , about 25 . 98° , about DSC FIG . 18 : extrapolated onset temperature for initial 22 . 15º , about 14 .41° , about 14 .60° , about 25 .57° , about 60 endotherm about 236° C ., followed by multiple thermal 13 . 12° , and about 19. 850 . One aspect of the present inven events tion is directed to a crystalline form of Compound 1 hemi DMS FIG . 19 : - 0 . 15 % weight gain at about 90 % RH fumarate salt having an X - ray powder diffraction pattern comprising one or more peaks listed in Table 10 . In some Compound 1 orotate salt , Form I was an anhydrous salt by embodiments , the crystalline form has an X -ray powder 65 TGA . The initial melting onset by DSC was 236° C . diffraction pattern substantially as shown in FIG . 14 , However , the initial endotherm was small and followed wherein by “ substantially ” is meant that the reported peaks immediately by a small exotherm which was followed US 10 ,226 ,471 B2 65 66 immediately by larger endothermic events . Based on TGA One aspect of the present invention is directed to a crystal results , there was significant weight loss occurring through - line form of Compound 1 orotate salt having an X -ray out these thermal events , indicating that the salt melted with powder diffraction pattern comprising one or more peaks decomposition . Compound 1 orotate salt was non -hygro - listed in Table 12 . In some embodiments , the crystalline scopic by DMS analysis , picking up about 0 . 15 % out to and 5 form has an X -ray powder diffraction pattern substantially as including the 90 % RH hold at 25° C . shown in FIG . 17 , wherein by “ substantially ” is meant that Certain X -ray powder diffraction peaks for Form I of the reported peaks can vary by about + 0 .2° 20 , and also that Compound 1 orotate salt are shown in Table 12 below . the relative intensities of the reported peaks can vary . In some embodiments , the crystalline form of Compound TABLE 12 1 orotate salt has a differential scanning calorimetry ther mogram comprising an endotherm with an extrapolated Pos . ( 20 ) Rel. Int. ( % ) onset temperature between about 220° C . and about 250° C . 6 . 30 73 . 29 In some embodiments, the crystalline form of Compound 1 9 .91 4 . 94 12 . 44 29 . 14 orotate salt has a differential scanning calorimetry thermo 14 . 59 20 . 96 15 gram comprising an endotherm with an extrapolated onset 14 . 86 22 . 50 temperature at about 236° C . In some embodiments , the 15 .29 18 . 32 crystalline form of Compound 1 orotate salt has a thermo 16 . 96 27 . 39 gravimetric analysis profile substantially as shown in FIG . 17 .89 9 .67 18 , wherein by " substantially ” is meant that the reported 18 .63 12 . 70 19 .62 37 . 19 20 TGA features can vary by about + 5° C . and by about + 2 % 19 .71 39 .63 weight change . 19 .93 18 .27 In some embodiments, the crystalline form of Compound 20 .44 7 .74 1 orotate salt has a differential scanning calorimetry ther 21. 57 15 .75 mogram substantially as shown in FIG . 18 , wherein by 22 .03 10 . 37 22 . 35 14 .64 25 " substantially ” is meant that the reported DSC features can 23 . 29 4 . 21 vary by about +6° C . and by about + 20 joules per gram . 24 .07 100 .00 In some embodiments, the crystalline form of Compound 24 . 55 23 .57 1 orotate salt has a dynamic moisture sorption profile 25 .02 23 .70 25 . 84 4 .42 substantially as shown in FIG . 19 , wherein by “ substan 26 .64 20 . 04 30 tially ” is meant that the reported DMS features can vary by 27 .36 11. 06 about 15 % relative humidity and by about 25 % weight 27 . 74 8 .30 change . 28 .09 10 .48 28 .64 28 . 74 Form I of Compound 1 orotate salt can be prepared by any 29 .14 19 . 54 of the suitable procedures known in the art for preparing 29 . 85 6 .78 35 crystalline polymorphs. In some embodiments Form I of 31. 40 3 .45 Compound 1 orotate salt can be prepared as described in 32. 04 3 . 34 Example 3 . 5 . In some embodiments , Form I of Compound 32 .53 5 . 46 33 . 80 8 .09 1 orotate salt can be prepared by slurrying crystalline 34 . 97 4 . 19 Compound 1 orotate salt containing one or more crystalline 35 . 33 4 . 53 40 forms other than Form I . In some embodiments , the crys 36 . 48 2 . 29 37 . 55 5 .27 talline form of Compound 1 orotate salt can be prepared by 38 . 25 2 . 26 recrystallizing crystalline Compound 1 orotate salt contain 38 .82 3 . 95 ing one or more crystalline forms other than Form I. 39 . 34 1 .66 Compound 1 Orotate Salt Hydrate 45 One aspect of the present invention pertains to a crystal One aspect of the present invention is directed to a line form of ( R ) - 8 - chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H crystalline form of Compound 1 orotate salt having an X - ray 3 -benzazepine orotate salt hydrate (Compound 1 orotate salt powder diffraction pattern comprising a peak , in terms of 20 . hydrate ). In some embodiments , the crystalline form of at about 24 .07º . In some embodiments, the crystalline form (R ) - 8 -chloro - 1 -methyl - 2 , 3 ,4 ,5 -tetrahydro - 1H - 3 -ben has an X -ray powder diffraction pattern comprising a peak , 50 zazepine orotate salt hydrate is Form 1 (Compound 1 orotate in terms of 20 , at about 6 .30º . In some embodiments , the salt hydrate , Form I) . The physical properties of Form I of crystalline form has an X - ray powder diffraction pattern Compound 1 orotate salt hydrate are summarized in Table 13 comprising peaks , in terms of 20 , at about 24 .07º and about below . 6 .30º . In some embodiments , the crystalline form has an X - ray powder diffraction pattern comprising peaks , in terms 55 TABLE 13 of 20 , at about 24 .07º and about 19 .71° . In some embodi ments , the crystalline form has an X - ray powder diffraction Compound 1 Orotate Salt Hydrate , Form I pattern comprising peaks, in terms of 20 , at about 24 . 07°, PXRD FIG . 20 : Peaks of 228 % relative intensity at 7 .43 , 7 .6774 , 13 . 35 , 15 . 25 , 16 . 28 , 18 . 31, 21. 47 , 22 .60 , 24 . 31, 24 .61 , and about 6 .30° , and about 19 .71° . In some embodiments , the 26 .67 °20 crystalline form has an X - ray powder diffraction pattern 60 TGA FIG . 21 : about 2 . 7 % weight loss up to about 147° C . and about comprising peaks , in terms of 20 , at about 24 .07° , about 0 . 9 % between about 147° C . and about 179° C . DSC FIG . 21: extrapolated onset temperature about 173° C . 6 . 30°, about 19 . 71°, about 19. 62° , about 12 . 44º, about corresponding to a melt / recrystallization ; extrapolated onset 28 .64° , and about 16 . 96º. In some embodiments , the crys temperature about 234° C . corresponding to a melt talline form has an X - ray powder diffraction pattern com decomposition prising peaks , in terms of 20 , at about 24 .07° , about 6 . 30° , 65 DMS FIG . 22 : - 0 . 14 % weight gain at about 90 % RH about 19. 71° , about 19 .62° , about 12 .44º , about 28 .64° , about 16 . 96º, about 25 .02° , about 24 .55° , and about 14 . 86º . US 10 , 226 , 471 B2 68 Compound 1 orotate salt hydrate had weight loss crystalline form has an X - ray powder diffraction pattern observed in two steps , the first ( 2 . 7 % )measured out to - 147° comprising a peak , in termsof 20, at about 21. 47º . In some C ., and the second ( 0 . 9 % ) occurring out to ~ 179° C . The embodiments , the crystalline form has an X - ray powder total weight loss (~ 3 .6 % ) was close to the theoretical amount diffraction pattern comprising peaks , in terms of 20 , at about for a 0 .75 (3 :4 )hydrate (3 .7 % ). The two step weight loss was 5 16 .28º and about 21. 47º . In some embodiments , the crys consistent with two H2O molecules having similar binding talline form has an X - ray powder diffraction pattern com energies that are different than the third H2O molecule in the prising peaks , in terms of 20 , at about 16 . 28º and about crystal lattice . A melting onset of ~ 234° C . by DSC scanned 7 .43° . In some embodiments , the crystalline form has an at 10° C ./ min followed an endotherm / exotherm melt/ crys X - ray powder diffraction pattern comprising peaks , in terms tallization at ~ 173° C . These thermal events are consistentmit 10 of 20 , at about 16 .28° , about 21. 47°, and about 7 .43° . In with conversion of the hydrated lattice to the anhydrous some embodiments, the crystalline form has an X -ray pow lattice and melting/ decomposition of anhydrous Compound der diffraction pattern comprising peaks , in terms of 20 , at 1 orotate , which was confirmed by removing a sample from about 16 . 28°, about 21. 47°, about 7 . 43°, about 26 .67° , about TGA after scanning to 200° C . and then running PXRD . 13 . 35º , about 7 .6774° , and about 18 .31° . In some embodi Compound 1 orotate salt hydrate , Form I was nonn . 15 ments , the crystalline form has an X - ray powder diffraction hygroscopic by DMS analysis , picking up about 0 . 14 % out pattern comprising peaks, in terms of 20 , at about 16 . 28°, about 21 . 47° , about 7 . 43° , about 26 .67º , about 13 . 35º , about to and including the 90 % RH hold at 25° . 7 .6774° , about 18 . 31°, about 15 .25° , about 24 . 31°, and Certain X -ray powder diffraction peaks for Form I of about 24 .61º . One aspect of the present invention is directed Compound 1 orotate salt hydrate are shown in Table 14 20 to a crystalline form of Compound 1 orotate salt hydrate below . having an X - ray powder diffraction pattern comprising one or more peaks listed in Table 14 . In some embodiments , the TABLE 14 crystalline form has an X - ray powder diffraction pattern Pos. (020 ) Rel . Int. ( % ) substantially as shown in FIG . 20 , wherein by " substan 7 . 43 78 .01 25 tially ” is meant that the reported peaks can vary by about 7 .68 42 .82 + 0 . 2° 20 , and also that the relative intensities of the reported 9 . 43 2 .77 peaks can vary . 10 . 77 1 . 07 In some embodiments, the crystalline form of Compound 12 . 91 25 . 56 1 orotate salt hydrate has a differential scanning calorimetry 13 . 35 45 . 76 14 .05 2 . 50 30 thermogram comprising an endotherm with an extrapolated 14 .71 10 . 30 onset temperature between about 160° C . and about 190° C . 15 . 25 35 .49 In some embodiments, the crystalline form of Compound 1 15 . 79 5 .69 orotate salt hydrate has a differential scanning calorimetry 16 . 28 100 .00 17 . 58 25 .45 thermogram comprising an endotherm with an extrapolated 18 . 31 41 . 37 onset temperature at about 173° C . In some embodiments , 18 . 78 17 .59 the crystalline form of Compound 1 orotate salt hydrate has 19 . 33 12 .83 a differential scanning calorimetry thermogram comprising 19 .85 7 .03 21. 47 91. 69 an endotherm with an extrapolated onset temperature 22. 08 24 . 23 between about 220° C . and about 250° C . In some embodi 22 . 60 28 . 39 40 ments , the crystalline form of Compound 1 orotate salt 22. 95 20 . 91 hydrate has a differential scanning calorimetry thermogram 23 . 99 11 . 59 24 . 31 29 .32 comprising an endotherm with an extrapolated onset tem 24 .61 29 . 10 perature at about 234° C . In some embodiments , the crys 25 . 02 4 . 66 talline form of Compound 1 orotate salt hydrate has a 25 .63 3 . 12 45 thermogravimetric analysis profile substantially as shown in 26 . 06 16 . 10 26 . 30 19 . 78 FIG . 21 , wherein by “ substantially ” is meant that the 26 . 67 56 . 52 reported TGA features can vary by about 15° C . and by 27 .21 8 .79 about + 2 % weight change . 27 .67 21 . 48 28 . 25 13 . 60 In some embodiments , the crystalline form of Compound 28 .84 26 .07 50 1 orotate salt hydrate has a differential scanning calorimetry 29. 52 26 . 20 thermogram substantially as shown in FIG . 21, wherein by 30 . 57 9 .68 " substantially ” is meant that the reported DSC features can 31. 13 13 . 31 vary by about + 6° C . and by about + 20 joules per gram . 31. 51 9 . 71 31 . 81 11 . 19 In some embodiments , the crystalline form of Compound 32 .79 2 . 68 55 1 orotate salt hydrate has a dynamic moisture sorption 33 .74 9 .94 profile substantially as shown in FIG . 22 , wherein by 34 . 00 8 . 50 “ substantially ” is meant that the reported DMS features can 34 .77 5 . 13 35 . 37 3 . 39 vary by about 25 % relative humidity and by about 25 % 36 . 11 1 . 06 weight change . 37 . 01 5 .26 60 Form I of Compound 1 orotate salt hydrate can be 38 .01 6 .71 prepared by any of the suitable procedures known in the art 39 .05 2 .24 for preparing crystalline polymorphs . In some embodiments Form I of Compound 1 orotate salt hydrate can be prepared One aspect of the present invention is directed to a as described in Example 3 . 6 . In some embodiments , Form I crystalline form of Compound 1 orotate salt hydrate having 65 of Compound 1 orotate salt hydrate can be prepared by an X - ray powder diffraction pattern comprising a peak , in slurrying crystalline Compound 1 orotate salt hydrate con terms of 20 , at about 16 .28º . In some embodiments , the taining one or more crystalline forms other than Form I . In US 10 ,226 ,471 B2 69 70 some embodiments , the crystalline form of Compound 1 TABLE 16 - continued orotate salt hydrate can be prepared by recrystallizing crys talline Compound 1 orotate salt hydrate containing one or Pos. ( °20 ) Rel. Int. ( % ) more crystalline forms other than Form I . 10 . 33 3 . 77 Compound 1 Di- 4 - acetamidobenzoate Salt - Cocrystal 5 10 .98 100 .00 12 . 31 19 . 40 Methyl Ethyl Ketone Solvate 12 .73 4 . 03 One aspect of the present invention pertains to a crystal 13 .22 2 .33 line form of ( R ) - 8 -chloro - 1 -methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H 13 .46 2 . 20 13 .90 3 .44 3 -benzazepine di- 4 - acetamidobenzoate salt - cocrystal 14 .73 1 . 33 methyl ethyl ketone solvate (Compound 1 di- 4 - acetamido 14 . 93 1. 57 benzoate salt -cocrystal methyl ethyl ketone solvate ) . In 15 .22 0 . 99 15 . 49 2 . 52 some embodiments, the crystalline form of ( R ) - 8 - chloro - 1 15 . 77 5 . 13 methyl- 2 , 3, 4 ,5 - tetrahydro - 1H -3 -benzazepine di- 4 -acetami 15 . 92 7 . 04 dobenzoate salt- cocrystal methyl ethyl ketone solvate is 15 16 .27 3 . 30 Form I (Compound 1 di- 4 - acetamidobenzoate salt - cocrystal 16 . 92 7 . 80 17 . 11 9 . 58 methyl ethylketone solvate, Form I ) . The physical proper 17 .51 2 . 41 ties of Form I of Compound 1 di- 4 - acetamidobenzoate 18 . 14 1 .45 salt - cocrystal methyl ethyl ketone solvate are summarized in 19 . 06 1 . 85 Table 15 below . 19 . 35 4 . 07 20 19 .60 7 .82 19 . 76 6 . 14 TABLE 15 20 .69 3 . 37 21. 02 1 . 10 Compound 1 Di- 4 -acetamidobenzoate Salt- Cocrystal 21 . 34 1 . 94 Methyl Ethyl Ketone Solvate , Form I 21. 48 2. 63 25 22 .06 3 . 89 PXRD FIG . 23 : Peaks of 27 % relative intensity at 5 . 19 , 6 .38 , 22 . 40 1 . 36 7 .46 , 10 . 98 , 12 .31 , 15 . 92 , 16 .92 , 17 . 11 , 19 .60 , 22 .73 , 23 . 84 , 22 . 58 4 . 80 and 24 . 26 °20 22 . 73 13 . 36 TGA FIG . 24 : about 2 . 7 % weight loss up to about 115° C . 22 .99 1 . 91 DSC FIG . 24 : extrapolated melting /desolvation onset 23 .54 4 .05 temperature about 113° C . ; enthalpy of fusion 89 J/ g 30 23 . 84 11 .04 DMS FIG . 25 : ~ 9 % weight gain at about 90 % RH 23 . 99 6 .46 24 . 26 10 .06 24 .53 2 .77 DSC analysis of Compound 1 di- 4 -acetamidobenzoate 24 .76 1 . 13 salt - cocrystalmethyl ethyl ketone solvate showed a melting / 25 .55 1 .01 desolvation onset temperature of 113° C . and an enthalpy of 35 25 . 93 1 . 90 fusion of 89 J / g . By TGA the sample lost approximately 26 . 10 3 . 17 26 . 51 4 . 92 2 . 7 % by weight during melting and continued to lose weight 26 .57 4 . 03 after the melt . 26 . 75 3 . 49 Compound 1 di- 4 - acetamidobenzoate salt - cocrystal 27 .02 1 . 74 27 .29 1 . 24 methyl ethyl ketone solvate , Form I did not pick up signifi - 40 27 . 54 0 . 36 cant weight below 70 % RH . The sample was hygroscopic 27 .93 0 . 29 above this point and picked up 2 . 6 % weight at 80 % RH and 28 . 29 1 . 76 over 9 % weight out to and including the 90 % RH hold at 25° 29 . 23 1 . 26 C . Hysteresis on the desorption isotherm indicated a pos 29 . 60 0 .49 30 .00 1 . 69 sible solid phase transition . The sample lost over 2 . 4 % 45 30 . 10 1 . 23 weight upon completion of the desorption phase , which had 30 .50 1 .00 not been removed during the drying step at 40° C . and ~ 1 % 30 .73 1 .02 31. 22 0 .76 RH . This is consistent with the weight loss seen in the TGA 31. 44 0 .69 upon melting suggesting that solvate solvent was lost during 31. 71 0 . 84 the DMS experiment. After DMS analysis the sample 50 31. 78 0 . 90 remained a white solid , however the PXRD pattern showed 32 . 16 0 . 90 32. 39 0 . 43 significant amorphous character and crystalline peaks con 32 .67 1 . 35 sistent with 4 - acetamidobenzoic acid rather than Compound 33. 00 0 .85 1 di- 4 - acetamidobenzoate salt. 33. 21 0 . 84 Certain X - ray powder diffraction peaks for Form I of 55 33 .78 0 .28 Compound 1 di- 4 - acetamidobenzoate salt - cocrystal methyl 34 . 26 0 . 52 34 .59 0 . 38 ethyl ketone solvate are shown in Table 16 below . 34 .72 0 .42 35 . 04 0 . 22 TABLE 16 35 . 48 0 . 37 35 .79 0 . 32 Pos. (°20 ) 36 . 28 0 . 29 Rel . Int. ( % ) 36 .56 0 .22 5 . 19 28 . 81 36 .79 0 .55 6 . 38 16 .51 37. 37 0 .87 6 .65 2 . 56 37 . 48 0 . 34 7 . 46 24 . 99 38 .07 0 .09 9 .07 4 . 73 38 .35 1 . 26 9 . 92 1 . 52 38 . 45 0 . 78