USOO9215895B2

(12) United States Patent (10) Patent No.: US 9,215,895 B2 BOWen et al. (45) Date of Patent: Dec. 22, 2015

(54) NICOTINE SALT FORMULATIONS FOR 2,231,909 A 2/1941 Hempel AEROSOL DEVICES AND METHODS 2.460,427 A 2, 1949 Musselman et al. 2,483,304. A 9/1949 Vogel THEREOF 2,502,561 A 4, 1950 Ebert 2,765,949 A 10, 1956 H.11 (71) Applicant: PAX Labs, Inc., San Francisco, CA 2,897,958 A 8, 1959 E. (US) 3,146,937 A 9, 1964 Vesak 3.420,360 A 1, 1969 Young (72) Inventors: Adam Bowen, San Francisco, CA (US); 3,567,014 A 3/1971 Feigelman Chenyue Xing, San Francisco, CA (US) 3,861,523 A 1/1975 Fountain et al. yu 9, s 3,941,300 A 3, 1976 Troth 4,207,976 A 6, 1980 Herman (73) Assignee: PAX Labs, Inc., San Francisco, CA 4,519,319 A 5, 1985 Howlett (US) 4,771,796 A 9/1988 Myer 4,798.310 A 1/1989 Kasai et al. c - r 4,813,536 A 3, 1989 Willis (*) Notice: patentSibi 1stO extended E. site or adjusted th still under 4,830,0284,836,224. A 6,5/1989 1989 Lawson et al. U.S.C. 154(b) by 0 days. 4,848,563 A 7/1989 Robbins 5,005,759 A 4, 1991 Bouche (21) Appl. No.: 14/512,311 5,123,530 A 6/1992 Lee 5,269,327 A 12/1993 Counts et al. 1-1. 5,605,226 A 2f1997 Hernlein (22) Filed: Oct. 10, 2014 5,641,064 A 6/1997 Goserud O O 5,746,587 A 5/1998 Racine et al. (65) Prior Publication Data 5,810,164 A 9, 1998 Rennecamp 5,881,884 A 3, 1999 Podosek US 2015/OO2O824A1 Jan. 22, 2015 5,938,018 A 8/1999 Keaveney et al. 5,967,310 A 10, 1999 H11 Related U.S. Application Data 5,975.415 A 11/1999 Zehnal 5,979,460 A 11/1999 Matsumura (63) Continuation of application No. 14/271,071, filed on 6,102,036 A 8/2000 Slutsky et al. May 6, 2014. 6,234,169 B1 5, 2001 Bulbrook et al. 6,269,966 B1 8/2001 Pallo et al. (60) Provisional application No. 61/912,507, filed on Dec. Continued 5, 2013, provisional application No. 61/820,128, filed (Continued) on May 6, 2013. FOREIGN PATENT DOCUMENTS (51) Int. Cl. CN 101869356 A 10/2010 A24F 47/00 (2006.01) CN 102754924. A 10, 2012 A24B 15/16 (2006.01) EP 0354661 A2 2/1990 A6 IK3 L/46.5 (2006.01) E. s: 3. A6 IK 9/12 (2006.01) EP 2325093 5, 2011 (52) U.S. Cl. EP 26098.21 A1 7, 2013 CPC ...... A24F 47/008 (2013.01); A24B 15/16 JP O2145179 11, 2000 (2013.01); A61 K9/12 (2013.01); A61 K3I/465 2001-165437 6, 2001 (2013 01) JP O9075058 9, 2007 WO WO97/12639 4f1997 (58) Field of Classification Search WO WOO3,O94900 11, 2003 CPC ...... A24F 47/OO8 WO WO 2011/033396 3, 2011 See application file for complete search history. WO WO 2011, 11758O 9, 2011 WO WO 2011, 139684 11, 2011 (56) References Cited WO WO 2012/021972 2, 2012 (Continued) U.S. PATENT DOCUMENTS OTHER PUBLICATIONS : A 13. Shy International search report and written opinion dated Sep. 5, 2014 for 595,070 A 12/1897 Oldenbusch PCT Application No. US2014/037019. 799,844 A 9, 1905 Fuller (Continued) 969,076 A 8, 1910 Pender 1,067,531 A 7/1913 MacGregor 1,163,183 A 12, 1915 Stoll Primary Examiner — Richard Crispino 1,299,162 A 4, 1919 Fisher Assistant Examiner — Dionne Walls Mayes 1,552,8771,505,748 A 9/19253, 1924 TamisPhillipps et al. (74) Attorney, Agent, or Firmriva — Shay Glenn LLP 1,632,335 A 6/1927 Hiering 1,706,244. A 3/1929 Meyerson (57) ABSTRACT 1,845,340 A 3. 1932 Ritz 11 A nicotine Salt liquid formulation for generating an inhalable E6. A 12: Money aerosol in an electronic cigarette comprising nicotine salt that 2,03363 A 2f1936 Erikson forms about 0.5% to about 20% nicotine is provided. 2,039,559 A 5/1936 Segal 2,327,120 A 11, 1940 McCoon 26 Claims, 8 Drawing Sheets US 9,215,895 B2 Page 2

(56) References Cited 2010, OOOO672 A1 1/2010 Fogle 2010.0031968 A1 2/2010 Sheikh et al. U.S. PATENT DOCUMENTS 2010, 0186757 A1 7, 2010 Crooks et al. 2010/0200.006 A1 8, 2010 Robinson et al. 6,386,371 B1 5, 2002 Parsons 2010/0242974 A1 9, 2010 Pan 6,431,363 B1 8, 2002 Hacker 2010/0242976 A1 9/2010 Katayama et al. 6,446,793 B1 9/2002 Layshock 2010/0275938 A1 11, 2010 Roth et al. 6,510,982 B2 1/2003 White et al. 2010/0276333 A1 11, 2010 Couture 6,557,708 B2 5, 2003 Polacco 2010/03071.16 A1 12/2010 Fisher 6,622,867 B2 9/2003 Menceles 2011/0049226 A1 3/2011 Moreau et al. 6,672,762 B1 1/2004 Faircloth 2011/O155153 A1 6/2011 Thorens et al. 6,726,006 B1 4/2004 Funderburk et al. 2011/0162667 A1 7/2011 Burke et al. 6,799,576 B2 10/2004 Farr 2011/O1681.94 A1 7, 2011 Hon 6,874,507 B2 4/2005 Farr 2011/0180433 A1 7/2011 Rennecamp 7,000,775 B2 2/2006 Gelardi 2011/O192397 A1 8/2011 Saskar et al. 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(56) References Cited Vansickel, et al. A clinical laboratory model for evaluating the acute effects of electronic "cigarettes': Nicotine delivery profile and car OTHER PUBLICATIONS diovascular and subjective effects. Cancer Epidemiol Biomarkers Prev. 19(8): 1945-53 (2010). Summary of evaluations performed by the Joint FAO/WHO expert Zhang, et al. In vitro particle size distributions in electronic and committee on food additive. (May 29, 2005)http://www.inchem.org/ conventional cigarette aerosols suggest comparable deposition pat documents/jecifalijeceval/jec 2181.htm. terns. Nicotine Tob Res. 15(2):501-8 (2013). Flouris, et al., Acute impact of active and passive electronic cigarette Communication Relating to the Results of the Partial International Smoking on serum cotinine and lung function. Toxicol. 25(2):91-101 Search for PCT/US2014/10390 16, dated Aug. 26, 2014 (7 pages). (2013). Anonymous: Any interest in determining nicotine by DVAP. Nov. 9. Goniewicz, et al., Nicotine levels in electronic cigarettes. Nicotine 2009. Tob Res. 15(1):158-66 (2013). PCT/US2014/037019 Third Party Observations and Comments filed Ingebrethsen, et al., Electronic cigarette aerosol particle size distri on Sep. 1, 2015. bution measurements. Inhal Toxicol. 24(14):976-84 (2012). International Search Report and Written Opinion dated Apr. 27, 2015 Seeman, et al., The form of nicotine in tobacco. Thermal transfer of for PCT Application No. PCT/US2014/072230. nicotine and nicotine acid salts to nicotine in the gas phase. J Agric Food Chem.47(12): 5133-45 (1999). * cited by examiner

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US 9,215,895 B2 1. 2 NCOTINE SALT FORMULATIONS FOR able liquid carrier wherein an acid used to form said nicotine AEROSOL DEVICES AND METHODS salt is characterized by vapor pressure >20 mmHg at 200°C. THEREOF Provided herein is a nicotine salt liquid formulation in an electronic cigarette for generating an inhalable aerosol upon CROSS REFERENCE heating in the electronic cigarette, the formulation in the cigarette comprising a nicotine Salt in a biologically accept This application is a continuation of U.S. patent applica able liquid carrier wherein an acid used to form said nicotine tion Ser. No. 14/271,071, filed May 6, 2014, which claims the salt is characterized by vapor pressure of about 20 to 200 benefit of U.S. Provisional Patent Application Ser. No. mmHg at 200° C. 61/820,128, filed May 6, 2013, and U.S. Provisional Patent 10 Provided herein is a nicotine salt liquid formulation in an Application Ser. No. 61/912,507, filed Dec. 5, 2013, all of electronic cigarette for generating an inhalable aerosol upon which are incorporated herein by reference in their entirety. heating in the electronic cigarette, the formulation in the SUMMARY OF THE INVENTION cigarette comprising a nicotine Salt in a biologically accept 15 able liquid carrier wherein an acid used to form said nicotine Provided herein is a method of delivering nicotine to a user salt is further characterized by a melting point <160° C., a comprising operating an electronic cigarette to a user wherein boiling point >160° C., and at least a 50-degree difference the electronic cigarette comprises a nicotine salt formulation between the melting point and the boiling point. comprising a nicotine salt in a biologically acceptable liquid Provided herein is a nicotine salt liquid formulation in an carrier wherein an acid used to form said nicotine salt is electronic cigarette for generating an inhalable aerosol upon characterized by vapor pressure >20 mmHg at 200°C., and heating in the electronic cigarette, the formulation in the inhaling an aerosol generated from the nicotine salt formula cigarette comprising a nicotine Salt in a biologically accept tion heated by the electronic cigarette. able liquid carrier wherein an acid used to form said nicotine Provided herein is a method of delivering nicotine to a user salt is further characterized by a melting point at least 40 comprising operating an electronic cigarette to a user wherein 25 degrees lower than an operating temperature of the electronic the electronic cigarette comprises a nicotine salt formulation cigarette, a boiling point no more than 40 degrees lower than comprising a nicotine salt in a biologically acceptable liquid the operating temperature of the electronic cigarette, and at carrier wherein an acid used to form said nicotine salt is leasta 50-degree difference between the melting point and the characterized by vapor pressure of about 20 to 200 mmHg at boiling point. 200°C., and inhaling an aerosol generated from the nicotine 30 Provided herein is a nicotine salt liquid formulation for salt formulation heated by the electronic cigarette. generating an inhalable aerosol upon heating in the electronic Provided herein is a method of delivering nicotine to a user cigarette, the nicotine salt liquid formulation comprising a comprising operating an electronic cigarette wherein the nicotine salt in a biologically acceptable liquid carrier electronic cigarette comprises a nicotine salt formulation wherein an acid used to form said nicotine salt is character comprising a nicotine salt in a biologically acceptable liquid 35 ized by vapor pressure >20 mmHg at 200° C. carrier wherein an acid used to form said nicotine salt is Provided herein is a nicotine salt liquid formulation for further characterized by a melting point <160° C., a boiling generating an inhalable aerosol upon heating in the electronic point >160° C., and at least a 50-degree difference between cigarette, the nicotine salt liquid formulation comprising a the melting point and the boiling point, and inhaling an aero nicotine salt in a biologically acceptable liquid carrier sol generated from the nicotine salt formulation heated by the 40 wherein an acid used to form said nicotine salt is character electronic cigarette. ized by vapor pressure of about 20 to 200 mmHg at 200°C. Provided herein is a method of delivering nicotine to a user Provided herein is a nicotine salt liquid formulation for comprising providing an electronic cigarette to a user generating an inhalable aerosol upon heating in the electronic wherein the electronic cigarette comprises a nicotine salt cigarette, the nicotine salt liquid formulation comprising a formulation comprising a nicotine salt in a biologically 45 nicotine salt in a biologically acceptable liquid carrier acceptable liquid carrier wherein an acid used to form said wherein an acid used to form said nicotine salt is further nicotine Salt is further characterized by a melting point at least characterized by a melting point <160° C., a boiling point 40 degrees lower than an operating temperature of the elec >160° C., and at least a 50-degree difference between the tronic cigarette, a boiling point no more than 40 degrees lower melting point and the boiling point. than the operating temperature of the electronic cigarette, and 50 Provided herein is a nicotine salt liquid formulation for at least a 50-degree difference between the melting point and generating an inhalable aerosol upon heating in the electronic the boiling point, and inhaling an aerosol generated from the cigarette, the nicotine salt liquid formulation comprising a nicotine salt formulation heated by the electronic cigarette. nicotine salt in a biologically acceptable liquid carrier Provided herein is a method of delivering nicotine to the wherein an acid used to form said nicotine salt is further blood of a user, said method comprising providing an aerosol 55 characterized by a melting point at least 40 degrees lower than that is inhaled by the user from an electronic cigarette that an operating temperature of the electronic cigarette, a boiling comprises a nicotine Salt formulation wherein providing the point no more than 40 degrees lower than the operating tem aerosol comprises the electronic cigarette heating the formu perature of the electronic cigarette, and at least a 50-degree lation thereby generating the aerosol, wherein the aerosol is difference between the melting point and the boiling point. effective in delivering a level of nicotine in the blood of the 60 Provided herein is a nicotine salt liquid formulation for use user that is at least 5 ng/mL at about 1.5 minutes after a first in an electronic cigarette the nicotine salt liquid formulation puff often puffs of the aerosol, each pufftaken at 30 second comprising a nicotine salt in a biologically acceptable liquid intervals. carrier wherein an acid used to form said nicotine Salt is Provided herein is a nicotine salt liquid formulation in an characterized by vapor pressure >20 mmHg at 200° C. electronic cigarette for generating an inhalable aerosol upon 65 Provided herein is a nicotine salt liquid formulation for use heating in the electronic cigarette, the formulation in the in an electronic cigarette the nicotine salt liquid formulation cigarette comprising a nicotine salt in a biologically accept comprising a nicotine salt in a biologically acceptable liquid US 9,215,895 B2 3 4 carrier wherein an acid used to form said nicotine salt is Provided herein is a cartomizer for an electronic cigarette characterized by vapor pressure of about 20 to 200 mmHg at comprising: 2009 C. a nicotine salt liquid formulation comprising a nicotine salt Provided herein is a nicotine salt liquid formulation for use in a biologically acceptable liquid carrier wherein an 5 acid used to form said nicotine salt is characterized by in an electronic cigarette the nicotine Salt liquid formulation vapor pressure >20 mmHg at 200°C.; comprising a nicotine salt in a biologically acceptable liquid an atomizer comprising a heating element in fluid commu carrier wherein an acid used to form said nicotine salt is nication with the nicotine salt liquid formulation; and further characterized by a melting point <160° C., a boiling a fluid storage compartment that stores the nicotine salt point >160° C., and at least a 50-degree difference between liquid formulation. the melting point and the boiling point. 10 Provided herein is a cartomizer for an electronic cigarette Provided herein is a nicotine salt liquid formulation for use comprising: in an electronic cigarette the nicotine Salt liquid formulation a nicotine salt liquid formulation comprising a nicotine salt comprising a nicotine salt in a biologically acceptable liquid in a biologically acceptable liquid carrier wherein an carrier wherein an acid used to form said nicotine salt is acid used to form said nicotine salt is characterized by 15 vapor pressure of about 20 to 200 mmHg at 200° C.; further characterized by a melting point at least 40 degrees an atomizer comprising a heating element in fluid commu lower than an operating temperature of the electronic ciga nication with the nicotine salt liquid formulation; and rette, a boiling point no more than 40 degrees lower than the a fluid storage compartment that stores the nicotine salt operating temperature of the electronic cigarette, and at least liquid formulation. a 50-degree difference between the melting point and the Provided herein is a cartomizer for an electronic cigarette boiling point. comprising: Provided herein is a use of a nicotine salt formulation for a nicotine salt liquid formulation comprising a nicotine salt delivery of nicotine to a user from an electronic cigarette in a biologically acceptable liquid carrier wherein an wherein the nicotine salt formulation comprises a nicotine acid used to form said nicotine salt is further character 25 ized by a melting point <160° C., a boiling point >160° salt in a biologically acceptable liquid carrier wherein an acid C., and at least a 50-degree difference between the melt used to form said nicotine salt is characterized by vapor ing point and the boiling point; pressure >20 mmHg at 200°C., and the nicotine salt formu an atomizer comprising a heating element in fluid commu lation is heated by the electronic cigarette to generate an nication with the nicotine salt liquid formulation; and aerosol inhalable by the user. a fluid storage compartment that stores the nicotine salt Provided herein is a use of a nicotine salt formulation for 30 liquid formulation. delivery of nicotine to a user from an electronic cigarette Provided herein is a cartomizer for an electronic cigarette wherein the nicotine salt formulation comprises a nicotine comprising: salt in a biologically acceptable liquid carrier wherein an acid a nicotine salt liquid formulation comprising a nicotine salt in a biologically acceptable liquid carrier wherein an used to form said nicotine salt is characterized by vapor 35 acid used to form said nicotine salt is further character pressure of about 20 to 200 mmHg at 200°C., and the nicotine ized by a melting point at least 40 degrees lower than an salt formulation is heated by the electronic cigarette to gen operating temperature of the electronic cigarette, a boil erate an aerosol inhalable by the user. ing point no more than 40 degrees lower than the oper Provided herein is a use of a nicotine salt formulation for ating temperature of the electronic cigarette, and at least delivery of nicotine to a user from an electronic cigarette 40 a 50-degree difference between the melting point and the wherein the nicotine salt formulation comprises a nicotine boiling point; salt in a biologically acceptable liquid carrier wherein an acid an atomizer comprising a heating element in fluid commu used to form said nicotine salt is further characterized by a nication with the nicotine salt liquid formulation; and melting point <160°C., a boiling point >160°C., and at least a fluid storage compartment that stores the nicotine salt a 50-degree difference between the melting point and the 45 liquid formulation. boiling point, and the nicotine Salt formulation is heated by Provided herein is an electronic cigarette for generating an the electronic cigarette to generate anaerosol inhalable by the inhalable aerosol comprising: USC. a fluid storage compartment; Provided herein is a use of a nicotine salt formulation for a heater; and delivery of nicotine to the blood of a user from an electronic 50 a nicotine salt liquid formulation in the fluid storage com cigarette, wherein the nicotine Salt formulation in the elec partment, the liquid formulation comprising a nicotine tronic cigarette is heated to form an aerosol which delivers a salt in a biologically acceptable liquid carrier wherein an level of nicotine in the blood of the user that is at least 5 ng/mL acid used to form said nicotine salt is characterized by at about 1.5 minutes after a first puff of ten puffs of the vapor pressure >20 mmHg at 200°C.; aerosol, each pufftaken at 30 second intervals. 55 a battery; and Provided herein is a use of a nicotine salt formulation for a mouthpiece. delivery of nicotine to a user from an electronic cigarette Provided herein is an electronic cigarette for generating an wherein the nicotine salt formulation comprises a nicotine inhalable aerosol comprising: salt in a biologically acceptable liquid carrier wherein an acid a fluid storage compartment; used to form said nicotine salt is further characterized by a 60 a heater; and melting point at least 40 degrees lower than an operating a nicotine salt liquid formulation in the fluid storage com temperature of the electronic cigarette, a boiling point no partment, the liquid formulation comprising a nicotine more than 40 degrees lower than the operating temperature of salt in a biologically acceptable liquid carrier wherein an the electronic cigarette, and at least a 50-degree difference acid used to form said nicotine salt is characterized by between the melting point and the boiling point, and the 65 vapor pressure of about 20 to 200 mmHg at 200° C.; nicotine salt formulation is heated by the electronic cigarette a battery; and to generate an aerosol inhalable by the user. a mouthpiece. US 9,215,895 B2 5 6 Provided herein is an electronic cigarette for generating an tine salt liquid formulation comprising a nicotine salt inhalable aerosol comprising: in a biologically acceptable liquid carrier wherein an a fluid storage compartment; acid used to form said nicotine Salt is characterized by a heater; and vapor pressure >20 mmHg at 200°C.; a nicotine salt liquid formulation in the fluid storage com iii. a heater, partment, the liquid formulation comprising a nicotine iv. a battery; and salt in a biologically acceptable liquid carrier wherein an V. a mouthpiece; and acid used to form said nicotine salt is further character (b) instructions for using the electronic cigarette to gener ized by a melting point <160°C., a boiling point >160° ate an inhalable aerosol. C., and at least a 50-degree difference between the melt 10 Provided herein is a kit comprising: ing point and the boiling point; (a) an electronic cigarette for generating an inhalable aero a battery; and Sol comprising a mouthpiece. i. a device body comprising a cartridge receptacle; Provided herein is an electronic cigarette for generating an ii. a cartridge comprising a fluid storage compartment, inhalable aerosol comprising: 15 wherein the fluid storage compartment stores a nico a fluid storage compartment; tine salt liquid formulation comprising a nicotine salt a heater; and in a biologically acceptable liquid carrier wherein an a nicotine salt liquid formulation in the fluid storage com acid used to form said nicotine Salt is characterized by partment, the liquid formulation comprising a nicotine vapor pressure of about 20 to 200 mmHg at 200° C.; salt in a biologically acceptable liquid carrier wherein an iii. a heater, acid used to form said nicotine salt is further character iv. a battery; and ized by a melting point at least 40 degrees lower than an V. a mouthpiece; and operating temperature of the electronic cigarette, a boil (b) instructions for using the electronic cigarette to gener ing point no more than 40 degrees lower than the oper ate an inhalable aerosol. ating temperature of the electronic cigarette, and at least 25 Provided herein is a kit comprising: a 50-degree difference between the melting point and the (a) an electronic cigarette for generating an inhalable aero boiling point; Sol comprising a battery; and i. a device body comprising a cartridge receptacle; a mouthpiece. ii. a cartridge comprising a fluid storage compartment, Provided herein is a cartridge in an electronic cigarette 30 wherein the fluid storage compartment stores a nico comprising a fluid storage compartment, wherein the fluid tine salt liquid formulation comprising a nicotine salt storage compartment stores a nicotine salt liquid formulation in a biologically acceptable liquid carrier wherein an comprising a nicotine salt in a biologically acceptable liquid acid used to form said nicotine Salt is further charac carrier wherein an acid used to form said nicotine salt is terized by a melting point <160° C., a boiling point characterized by vapor pressure >20 mmHg at 200° C. 35 >160° C., and at least a 50-degree difference between Provided herein is a cartridge in an electronic cigarette the melting point and the boiling point; comprising a fluid storage compartment, wherein the fluid iii. a heater, storage compartment stores a nicotine salt liquid formulation iv. a battery; and comprising a nicotine salt in a biologically acceptable liquid V. a mouthpiece; and carrier wherein an acid used to form said nicotine salt is 40 (b) instructions for using the electronic cigarette to gener characterized by vapor pressure of about 20 to 200 mmHg at ate an inhalable aerosol. 2009 C. Provided herein is a kit comprising: Provided herein is a cartridge in an electronic cigarette (a) an electronic cigarette for generating an inhalable aero comprising a fluid storage compartment, wherein the fluid Sol comprising storage compartment stores a nicotine salt liquid formulation 45 i. a device body comprising a cartridge receptacle; comprising a nicotine salt in a biologically acceptable liquid ii. a cartridge comprising a fluid storage compartment, carrier wherein an acid used to form said nicotine salt is wherein the fluid storage compartment stores a nico further characterized by a melting point <160° C., a boiling tine salt liquid formulation comprising a nicotine salt point >160° C., and at least a 50-degree difference between in a biologically acceptable liquid carrier wherein an the melting point and the boiling point. 50 acid used to form said nicotine Salt is further charac Provided herein is a cartridge in an electronic cigarette terized by a melting point at least 40 degrees lower comprising a fluid storage compartment, wherein the fluid than an operating temperature of the electronic ciga storage compartment stores a nicotine salt liquid formulation rette, a boiling point no more than 40 degrees lower comprising a nicotine salt in a biologically acceptable liquid than the operating temperature of the electronic ciga carrier wherein an acid used to form said nicotine salt is 55 rette, and at least a 50-degree difference between the further characterized by a melting point at least 40 degrees melting point and the boiling point; lower than an operating temperature of the electronic ciga iii. a heater, rette, a boiling point no more than 40 degrees lower than the iv. a battery; and operating temperature of the electronic cigarette, and at least V. a mouthpiece; and a 50-degree difference between the melting point and the 60 (b) instructions for using the electronic cigarette to gener boiling point. ate an inhalable aerosol. Provided herein is a kit comprising: (a) an electronic cigarette for generating an inhalable aero INCORPORATION BY REFERENCE Sol comprising i. a device body comprising a cartridge receptacle; 65 All publications, patents and patent applications men ii. a cartridge comprising a fluid storage compartment, tioned in this specification are herein incorporated by refer wherein the fluid storage compartment stores a nico ence to the same extent as if each individual publication, US 9,215,895 B2 7 8 patent or patent application was specifically and individually peak concentration of the nicotine in the blood and total indicated to be incorporated by reference. amount of nicotine delivered appears comparable to a tradi tional cigarette, and do not appear to vary significantly BRIEF DESCRIPTION OF THE DRAWINGS between the various nicotine formulations. Therefore, described herein are nicotine salt formulations for use in an A better understanding of the features and advantages of electronic cigarette, or the like, that provide a general satis the present invention will be obtained by reference to the faction effect consistent with an efficient transfer of nicotine following detailed description that sets forth illustrative to the lungs of an individual and a rapid rise of nicotine embodiments, in which the principles of the invention are absorption in the plasma. Provided herein, therefore, are used, and the accompanying drawings of which: 10 devices, formulation of nicotine salts, systems, cartomizers, FIG. 1 illustrates results of heart rate data measured for six kits and methods that are used to inhale an aerosol generated minutes from start of puffing. Y-axis is heart rate (bpm) and from a nicotine Salt liquid formulation through the mouth or X-axis represent duration of the test (-60 to 180 seconds); nose as described herein or as would be obvious to one of skill FIG. 2 illustrates results of heart rate data measured for ten in the art upon reading the disclosure herein. minutes from start of puffing. Y-axis is heart rate (bpm) and 15 Consistent with these satisfaction effects, it has unexpect X-axis represents duration of the test (0 to 10 minutes); edly been found herein that there is a difference between the FIG. 3 illustrates the calculated vapor pressures of various C (maximum concentration) and T (time at which the acids relative to nicotine; maximum concentration is measured) when measuring blood FIG. 4 illustrates the pharmacokinetic profiles foreight test plasma nicotine levels of freebase nicotine formulations articles in a blood plasma study: inhaled using a low temperature vaporization device, i.e. elec FIG. 5 illustrates the comparison of Cand T foreight tronic cigarette, as compared to the C and T (similarly test articles in a blood plasma study: measuring blood plasma nicotine levels) of a traditional ciga FIG. 6 illustrates the comparison of C and AUC for rette. Also consistent with these satisfaction effects, it has eight test articles in a blood plasma study: unexpectedly been found herein that there is a difference FIG. 7 depicts an example embodiment of an electronic 25 between the C(maximum concentration) and T (time at cigarette having a fluid storage compartment comprising an which the maximum concentration is measured) when mea embodiment nicotine salt formulation described herein; and suring blood plasma nicotine levels of freebase nicotine for FIG. 8 depicts an example embodiment of an electronic mulations inhaled using a low temperature vaporization cigarette cartomizer having a fluid storage compartment, a device, i.e. electronic cigarette, as compared to the C and heater, and comprising an embodiment nicotine salt formu 30 T (similarly measuring blood plasma nicotine levels) of lation described herein. nicotine salt formulations inhaled using a low temperature vaporization device, i.e. electronic cigarette. Additionally, it DETAILED DESCRIPTION OF THE INVENTION has unexpectedly been found that there is a difference between the rate of nicotine uptake in the plasma of users Nicotine is a chemical stimulant and increases heart rate 35 inhaling freebase nicotine formulations using a low tempera and blood pressure when provided to an individual or animal. ture vaporization device, i.e. electronic cigarette, as com Nicotine transfer to an individual is associated with a feeling pared to the rate of nicotine uptake in the plasma of users of physical and/or emotional satisfaction. Conflicting reports inhaling Smoke of a traditional cigarette. Furthermore, it has have been published regarding the transfer efficiency of free unexpectedly been found that there is a difference between base nicotine in comparison to mono- or di-protonated nico 40 the rate of nicotine uptake in the plasma of users inhaling tine salts. Studies on the transfer efficiency of free base nico freebase nicotine formulations using a low temperature tine and nicotine salts are complex and have yielded unpre vaporization device, i.e. electronic cigarette, as compared to dictable results. Further, such transfer efficiency studies have the rate of nicotine uptake in the plasma of users inhaling been performed under extremely high temperature condi nicotine salt formulations using a low temperature vaporiza tions, comparable to Smoking; therefore, they offer scant 45 tion device, i.e. electronic cigarette. guidance on the transfer efficiency of free base nicotine and Thus, looking at freebase nicotine as a source of nicotine in nicotine salts under low-temperature vaporization conditions. compositions used in e-cigarettes, freebase nicotine compo Some reports have posited that nicotine free base should give sitions delivery of nicotine to blood when inhaled using is rise to a greater satisfaction in a user than any corresponding not necessarily comparable in blood plasma levels (C. and nicotine salt. 50 T) to a traditional cigarette's nicotine delivery to blood It has been unexpectedly discovered herein that certain when inhaled. Freebase nicotine compositions delivery of nicotine salt formulations provide satisfaction in an indi nicotine to blood when inhaled using is not necessarily com vidual Superior to that of free base nicotine, and more com parable in blood plasma levels (Cand T) to nicotine salt parable to the satisfaction in an individual Smoking a tradi formulations’ nicotine delivery to blood when inhaled. Free tional cigarette. The satisfaction effect is consistent with an 55 base nicotine compositions delivery of nicotine to blood efficient transfer of nicotine to the lungs of an individual and when inhaled using is not necessarily comparable in blood a rapid rise of nicotine absorption in the plasma as shown, for plasma levels when measuring the rate of nicotine uptake in non-limiting example, in Example 8, at least. It has also been the blood within the first 0-5 minutes to a traditional ciga unexpectedly discovered herein that certain nicotine salt for rette's nicotine delivery to blood when inhaled. Freebase mulations provide greater satisfaction than other nicotine salt 60 nicotine compositions delivery of nicotine to blood when formulations, and Such effect has been shown in blood plasma inhaled using necessarily is not comparable in blood plasma levels of example nicotine salt formulations herein, for non levels when measuring the rate of nicotineuptake in the blood limiting example, in Example 8, at least. These results show a within the first 0-5 minutes to nicotine salt formulations difference in rate of nicotine uptake in the blood that is higher nicotine delivery to blood when inhaled. for Some nicotine salt formulations aerosolized by an elec 65 Also consistent with these satisfaction effects, it has unex tronic cigarette than for other nicotine salt formulations, and pectedly been found herein that while there appears to be likewise higher than nicotine freebase formulations, while the comparable C, and T. Values (measuring blood plasma US 9,215,895 B2 10 nicotine levels) of nicotine salt formulations inhaled using a other nicotine salt formulations, however, they also provide low temperature vaporization device, i.e. electronic cigarette, satisfaction comparable to a traditional cigarette or closer to a as compared to the Cand T (similarly measuring blood traditional cigarette (as compared to other nicotine Salt for plasma nicotine levels) of a traditional cigarette, there is a mulations or as compared to nicotine freebase formulations). demonstrable difference between the rate of nicotine uptake Operating temperature can be 100° C. to 300° C., or about in the plasma of users inhaling certain nicotine salt formula 200° C., about 150° C. to about 250° C., 180 C to 220° C., tions using a low temperature vaporization device, i.e. elec about 180° C. to about 220° C., 185°C. to 215° C., about 185° tronic cigarette, as compared to the rate of nicotine uptake in C. to about 215° C., about 190° C. to about 210°C., 190° C. the plasma of users inhaling other nicotine salt formulations to 210°C., 195°C. to 205° C., or about 195° C. to about 205° using a low temperature vaporization device, i.e. electronic 10 cigarette. It is also unexpected that while the C and T. C. For non-limiting example, acids that meet the criteria of values are comparable to those of a traditional cigarette, (or the prior sentence include salicylic acid, Sorbic acid, benzoic are approaching that of a traditional cigarette), the rate of acid, pyruvic acid, lauric acid, and levulinic acid. Combina nicotine uptake in the plasma of blood of users is higher in tions of these criteria for preference of certain nicotine salt certain nicotine salt formulations than that of the traditional 15 formulations are contemplated herein. cigarette. The nicotine salt formulations which demonstrate Other reasons for excluding certain acids from formula the quickest rate of nicotine uptake in the plasma were more tions may be unrelated to the rate of nicotine uptake, however. preferred in satisfaction evaluations, and were rated more For example, an acid may be inappropriate for use with the equivalent to cigarette satisfaction than the nicotine salt for device materials (corrosive or otherwise incompatible). Sul mulations showing the slowest rates of rise of nicotine in the furic acid is an example of this, which may be inappropriate Subjects blood plasma. In addition, doubling the concentra for the e-cigarette device. An acid may be inappropriate for tion of the nicotine salt in the formulation may not necessarily use in inhalation or for toxicity reasons—thus not be compat impact the rate of absorption of nicotine in the blood (see, for ible for human consumption, ingestion, or inhalation. Sulfu non-limiting Example 8, nicotine benzoate tested in 4% and ric acid again is an example of this, which may be inappro 2% concentrations). 25 priate for a user of an e-cigarette device, depending on the Thus, looking at nicotine Salt formulations used in e-ciga embodiment of the composition. An acid that is bitter or rettes, nicotine Salt formulations delivered using an e-ciga otherwise bad-tasting may also provide a reason for exclu rette appear comparable in C, and T. Values (measuring Sion, Such as acetic acid in Some embodiments. Acids that blood plasma nicotine levels), however, not all nicotine salts oxidize at room temperature or at operating temperature may perform similarly to each other or to a traditional cigarette 30 be inappropriate for certain embodiments, for example, Sor with respect to the rate of nicotineuptake in the blood at early bic acid, as this indicates a decomposition or reaction or time periods (0-1.5 minutes). These results are unexpected. instability that may be undesirable in the formulation. Nicotine salt formulations made using acids having a Vapor Decomposition of acids at room or operating temperatures Pressure between 20-300 mmHg (a) 200° C., or Vapor Pres may also indicate that the acid is inappropriate for use in the sure >20 mmHg (a) 200° C., or a Vapor Pressure from 20 to 35 embodiment formulations. For example, citric acid decom 300 mmHg (a) 200° C., or a Vapor Pressure from 20 to 200 poses at 175°C., and malic acid decomposes at 140°C., thus mmHg (a) 200° C., a Vapor Pressure between 20 and 300 for a device operating at 200° C., these acids may not be mmHg (a) 200° C. appear to have a higher rate of nicotine appropriate. Acids that have poor solubility in the composi uptake in the blood at early time periods (0-1.5 minutes, 0-3 tion constituents may be inappropriate for use in certain minutes, 0-2 minutes, 0-4 minutes for non-limiting example) 40 embodiments of the compositions herein. For example, nico than other nicotine salt formulations, however, they also pro tine bitartrate with a composition of nicotine and tartaric acid vide satisfaction comparable to a traditional cigarette or as 1:2 molar ratio will not produce a solution at a concentra closer to a traditional cigarette (as compared to other nicotine tion of 0.5%(w/w) nicotine or higher and 0.9%(w/w) tartaric salt formulations or as compared to nicotine freebase formu acid or higher in propylene glycol (PG) or vegetable glycerin lations). For non-limiting example, acids that meet one or 45 (VG) or any mixture of PG and VG at ambient conditions. As more criteria of the prior sentence include salicylic acid, used herein, weight percentage (w/w) refers to the weight of Sorbic acid, benzoic acid, lauric acid, and levulinic acid. the individual component over the weight of the total formu Nicotine salt formulations made using acids that have a dif lation. ference between boiling point and melting point of at least As used in this specification and the claims, the singular 50° C., and a boiling point greater than 160°C., and a melting 50 forms “a,” “an and “the include plural referents unless the point less than 160° C. appear to have a higher rate of nicotine context clearly dictates otherwise. uptake in the blood at early time periods (0-1.5 minutes, 0-3 The term “organic acid as used herein, refers to an organic minutes, 0-2 minutes, 0-4 minutes for non-limiting example) compound with acidic properties (e.g., by Bronsted-Lowry than other nicotine salt formulations, however, they also pro definition, or Lewis definition). A common organic acid is the vide satisfaction comparable to a traditional cigarette or 55 carboxylic acids, whose acidity is associated with their car closer to a traditional cigarette (as compared to other nicotine boxyl group —COOH. A dicarboxylic acid possesses two salt formulations or as compared to nicotine freebase formu carboxylic acid groups. The relative acidity of an organic is lations). For non-limiting example, acids that meet the criteria measured by its pK value and one of skill in the art knows of the prior sentence include Salicylic acid, Sorbic acid, ben how to determine the acidity of an organic acid based on its Zoic acid, pyruvic acid, lauric acid, and levulinic acid. Nico 60 given pKa value. The term “keto acid as used herein, refers tine Salt formulations made using acids that have a difference to organic compounds that contain a carboxylic acid group between boiling point and melting point of at least 50°C., and and a ketone group. Common types of keto acids include a boiling point at most 40°C. less than operating temperature, alpha-keto acids, or 2-oxoacids, Such as pyruvic acid or and a melting point at least 40° C. lower than operating oxaloacetic acid, having the keto group adjacent to the car temperature appear to have a higher rate of nicotine uptake in 65 boxylic acid; beta-keto acids, or 3-oxoacids, such as the blood at early time periods (0-1.5 minutes, 0-3 minutes, acetoacetic acid, having the ketone group at the second car 0-2 minutes, 0-4 minutes for non-limiting example) than bon from the carboxylic acid, gamma-keto acids, or 4-oxoac US 9,215,895 B2 11 12 ids. Such as levulinic acid, having the ketone group at the third concentration of a second nicotine salt. In some formulations, carbon from the carboxylic acid. the concentration of nicotine in the first nicotine salt formu The term "electronic cigarette' or “e-cigarette' or “low lation is about 1% to about 20%, and is combined with a temperature vaporization device' as used herein, refers to an second nicotine Salt formulation having a concentration of electronic inhaler that vaporizes a liquid Solution into an 5 nicotine therein from about 1% to about 20% or any range or aerosol mist, simulating the act of tobacco Smoking. The concentration therein. In some formulations, the concentra liquid solution comprises a formulation comprising nicotine. tion of nicotine in the first nicotine salt formulation is 1% to There are many electronic cigarettes which do not resemble 20%, and is combined with a second nicotine salt formulation conventional cigarettes at all. The amount of nicotine con having a concentration of nicotine therein from 1% to 20% or tained can be chosen by the user via the inhalation. In general, 10 an electronic cigarette contains three essential components: a any range or concentration therein. As used with respect to plastic cartridge that serves as a mouthpiece and a reservoir concentrations of nicotine in the nicotine salt formulations, for liquid, an "atomizer” that vaporizes the liquid, and a the term “about” refers to ranges of 0.05% (i.e. if the concen battery. Other embodiment electronic cigarettes include a tration is about 2%, the range is 1.95%-2.05%), 0.1 (i.e. if the combined atomizer and reservoir, called a “cartomizer” that 15 concentration is about 2%, the range is 1.9%-2.1%), 0.25 (i.e. may or may not be disposable, a mouthpiece that may be if the concentration is about 2%, the range is 1.75%-2.25%), integrated with the cartomizer or not, and a battery. 0.5 (i.e. if the concentration is about 2%, the range is 1.5%- As used in this specification and the claims, unless other 2.5%), or 1 (i.e. if the concentration is about 4%, the range is wise stated, the term “about” refers to variations of 1%, 2%, 3%-5%), depending on the embodiment. 3%, 4%, 5%, 10%, 15%, or 25%, depending on the embodi Nicotine salts are formed by the addition of a suitable acid, ment. including organic or inorganic acids. In some formulations Suitable carriers (e.g., a liquid solvent) for the nicotine provided herein, Suitable organic acids are carboxylic acids. salts described herein include a medium in which a nicotine Examples of organic carboxylic acids disclosed herein are salt is soluble at ambient conditions, such that the nicotine salt monocarboxylic acids, dicarboxylic acids (organic acid con does not form a solid precipitate. Examples include, but are 25 taining two carboxylic acid groups), carboxylic acids con not limited to, glycerol, propylene glycol, trimethylene gly taining an aromatic group Such as benzoic acids, hydroxycar col, water, ethanol and the like, as well as combinations boxylic acids, heterocyclic carboxylic acids, terpenoid acids, thereof. In some embodiments, the liquid carrier comprises Sugar acids; such as the pectic acids, amino acids, 0% to 100% of propylene glycoland 100% to 0% of vegetable cycloaliphatic acids, aliphatic carboxylic acids, keto car glycerin. In some embodiments, the liquid carrier comprises 30 boxylic acids, and the like. In some formulations provided 10% to 70% of propylene glycoland 90% to 30% of vegetable herein, the organic acids used herein are monocarboxylic glycerin. In some embodiments, the liquid carrier comprises acids. Nicotine salts areformed from the addition of a suitable 20% to 50% of propylene glycoland 80% to 50% of vegetable acid to nicotine. In some formulations provided herein, the glycerin. In some embodiments, the liquid carrier comprises Stoichiometric ratios of the nicotine to acid (nicotine:acid) are 30% propylene glycol and 70% vegetable glycerin. 35 1:1, 1:2, 1:3, 1:4, 2:3, 2:5, 2:7, 3:4, 3:5, 3:7, 3:8, 3:10, 3:11, The formulations described herein vary in concentration. 4:5, 4:7, 4:9, 4:10, 4:11, 4:13, 4:14, 4:15, 5:6, 5:7, 5:8, 5:9, In some formulations, a dilute concentration of the nicotine 5:11, 5:12, 5:13, 5:14, 5:16, 5:17, 5:18, or 5:19. In some salt in the carrier is utilized. In some formulations, a less formulations provided herein, the stoichiometric ratios of the dilute concentration of the nicotine salt in the carrier is uti nicotine to acid are 1:1, 1:2, 1:3, or 1:4 (nicotine:acid). lized. In some formulations the concentration of nicotine in 40 Nicotine is an alkaloid molecule that comprises two basic the nicotine salt formulation is about 1% (w/w) to about 25% nitrogens. It may occur in different states of protonation. For (w/w). In some formulations the concentration of nicotine in example, if no protonation exists, nicotine is referred to as the the nicotine salt formulation is about 1% (w/w) to about 20% “free base.” If one nitrogen is protonated, then the nicotine (w/w). In some formulations the concentration of nicotine in would be "mono-protonated.” the nicotine salt formulation is about 1% (w/w) to about 18% 45 Nicotine salt formulations may be formed by adding a (w/w). In some embodiments the concentration of nicotine in Suitable acid to nicotine, stirring the neat mixture at ambient the nicotine salt formulation is about 1% (w/w) to about 15% temperature or at elevated temperature, and then diluting the (w/w). In some formulations the concentration of nicotine in neat mixture with a carrier mixture. Such as a mixture of the nicotine salt formulation is about 4% (w/w) to about 12% propylene glycol and glycerin. In some embodiments, the (w/w). In some formulations the concentration of nicotine in 50 suitable acid is completely dissolved by the nicotine prior to the nicotine salt formulation is about 4% (w/w). In some dilution. The suitable acid may not completely dissolved by embodiments the concentration of nicotine in the nicotine salt the nicotine prior to dilution. The addition of the suitable acid formulation is about 2% (w/w). In some formulations the to the nicotine to form a neat mixture may cause an exother concentration of nicotine in the nicotine salt formulation is mic reaction. The addition of the suitable acid to the nicotine 1% (w/w) to 25% (w/w). In some formulations the concen 55 to form a neat mixture may be conducted at 55° C. The tration of nicotine in the nicotine salt formulation is 1% (w/w) addition of the suitable acid to the nicotine to form a neat to 20% (w/w). In some formulations the concentration of mixture may be conducted at 90°C. The neat mixture may be nicotine in the nicotine salt formulation is 1% (w/w) to 18% cooled to ambient temperature prior to dilution. The dilution (w/w). In some formulations the concentration of nicotine in may be carried out at elevated temperature. the nicotine salt formulation is 1% (w/w) to 15% (w/w). In 60 Nicotine salt formulations may be prepared by combining Some formulations the concentration of nicotine in the nico nicotine and a suitable acid in a carrier mixture, Such as a tine salt formulation is 4% (w/w) to 12% (w/w). In some mixture of propylene glycol and glycerin. The mixture of formulations the concentration of nicotine in the nicotine salt nicotine and a first carrier mixture is combined with a mixture formulation is 4% (w/w). In some formulations the concen ofa Suitable acid in a second carrier mixture. In some embodi tration of nicotine in the nicotine salt formulation is 2% 65 ments, the first and second carrier mixtures are identical in (w/w). In some formulations, a less dilute concentration of composition. In some embodiments, the first and second car one nicotine salt is used in conjunction with a more dilute rier mixtures are not identical in composition. In some US 9,215,895 B2 13 14 embodiments, heating of nicotine/acid/carrier mixture is salt may be best performing when it is at its optimal extent of required to facilitate complete dissolution. protonation, depending on the salt. For example, nicotine In some embodiments, nicotine salt formulations may be pyruvate is a nicotine salt with 1:2 nicotine:acid ratio. The prepared and added to a solution of 3:7 ratio by weight of formulation containing nicotine pyruvate (1:2) may deliver propylene glycol (PG)/vegetable glycerin (VG), and mixed 5 more satisfaction to the user than the one containing same thoroughly. While described herein as producing 10g of each amount of nicotine but only half amount of pyruvic acid, i.e. of the formulations, all procedures noted infra are scalable. nicotine pyruvate (1:1). This may be explained as 1 mole of Other manners of formulation may also be employed form the nicotine produces a salt with 2 moles of pyruvic acid. When formulations noted infra, without departing from the disclo there is not enough pyruvic acid to associate with all nicotine sure herein, and as would be known to one of skill in the art 10 upon reading the disclosure herein. molecules, the free base nicotine left unprotonated in the The optimal nicotine salt formulation may be determined formulation may reduce the satisfaction the formulation pro by the vapor pressure of the constituent acid. In some embodi vides. ments, the nicotine salt formulations comprise an acid with a The flavor of the constituent acid used in the salt formation vapor pressure that is similar to the vapor pressure of free base 15 may be a consideration in choosing the acid. A Suitable acid nicotine. In some embodiments, the nicotine salt formula may have minimal or no toxicity to humans in the concentra tions are formed from an acid with a vapor pressure that is tions used. A suitable acid may be compatible with the elec similar to the vapor pressure of free base nicotine at the tronic cigarette components it contacts or could contact at the heating temperature of the device. FIG.3 illustrates this trend. concentrations used. That is, such acid does not degrade or Nicotine salts formed from nicotine and benzoic acid; nico otherwise react with the electronic cigarette components it tine and salicylic acid; or nicotine and levulinic acid are salts contacts or could contact. The odor of the constituent acid that produce a satisfaction in an individual user consistent used in the salt formation may be a consideration in choosing with efficient transfer of nicotine and a rapid rise in nicotine a suitable acid. The concentration of the nicotine salt in the plasma levels. This pattern may be due to the mechanism of carrier may affect the satisfaction in the individual user. In action during heating of the nicotine salt formulation. The 25 some embodiments, the flavor of the formulation is adjusted nicotine salt may disassociate at, or just below, the heating by changing the acid. In some embodiments, the flavor of the temperature of the device, resulting in a mixture of free base formulation is adjusted by adding exogenous flavorants. In nicotine and the individual acid. At that point, if both the Some embodiments, an unpleasant tasting or Smelling acid is nicotine and acid have similar vapor pressures, they may used in minimal quantities to mitigate such characteristics. In aerosolize at the same time, giving rise to a transfer of both 30 Some embodiments, exogenous pleasant Smelling or tasting free base nicotine and the constituent acid to the user. acid is added to the formulation. Examples of salts which can The nicotine salt liquid formulation for generating an provide flavor and aroma to the mainstream aerosol at certain inhalable aerosol upon heating in an electronic cigarette may levels include nicotine acetate, nicotine oxalate, nicotine comprise a nicotine Salt in a biologically acceptable liquid malate, nicotine isovalerate, nicotine lactate, nicotine citrate, carrier; wherein the acid used to form said nicotine salt is 35 nicotine phenylacetate and nicotine myristate. characterized by a vapor pressure between 20-4000 mmHg at Nicotine salt formulations may generate an inhalable aero 200° C. In some embodiments, the acid used to form the Sol upon heating in an electronic cigarette. The amount of nicotine salt is characterized by vapor pressure between nicotine or nicotine salt aerosol inhaled may be user-deter 20-2000 mmHg at 200°C. In some embodiments, the acid mined. The user may, for example, modify the amount of used to form the nicotine salt is characterized by vapor pres 40 nicotine or nicotine salt inhaled by adjusting his inhalation sure between 100-300 mmHg at 200° C. strength. Unexpectedly, different nicotine salt formulations pro Formulations are described herein comprising two or more duced varying degrees of satisfaction in an individual. In nicotine salts. In some embodiments, wherein a formulation Some embodiments, the extent of protonation of the nicotine comprises two or more nicotine salts, each individual nicotine salt affected satisfaction, such that more protonation was less 45 salt is formed as described herein. satisfying as compared to less protonation. The nicotine salt Nicotine salt formulations, as used herein, refer to a single formed may be monoprotonated. The nicotine salt formed or mixture of nicotine salts with other suitable chemical com may be diprotonated. The nicotine Salt may exist in more than ponents used fore-cigarette, such as carriers, stabilizers, dilu one protonation state, e.g., an equilibrium of mono-proto ents, dispersing agents, Suspending agents, thickening agents, nated and di-protonated nicotine salts. The extent of protona 50 and/or excipients. In certain embodiments, the nicotine salt tion of the nicotine molecule may be dependent upon the formulation is stirred at ambient conditions for 20 minutes. In Stoichiometric ratio of nicotine:acid used in the salt formation certain embodiments, the nicotine salt formulation is heated reaction. The extent of protonation of the nicotine molecule and stirred at 55 C for 20 minutes. In certain embodiments, may be dependent upon the solvent. The extent of protonation the nicotine salt formulation is heated and stirred at 90 C for of the nicotine molecule may be unknown. In some embodi 55 60 minutes. In certain embodiments, the formulation facili ments, monoprotonated nicotine salts produced a high degree tates administration of nicotine to an organism (e.g., lung). of satisfaction in the user. For example, nicotine benzoate and The nicotine of nicotine salt formulations provided herein nicotine Salicylate are mono-protonated nicotine salts and all is either naturally occurring nicotine (e.g., from extract of produce a high degree of satisfaction in the user. The reason nicotineous species such as tobacco), or synthetic nicotine. In for this trend may be explained by a mechanism of action 60 Some embodiments, the nicotine is (-)-nicotine, (+)-nicotine, wherein the nicotine is first deprotonated prior to transfer to or a mixture thereof. In some embodiments, the nicotine is the vapor with the constituent acid and then retained and employed in relatively pure form (e.g., greater than about stabilized after re-protonated by the acid going down stream 80% pure, 85% pure, 90% pure, 95% pure, or 99% pure). In to the lungs of the user. It may be easier to remove one proton Some embodiments, the nicotine for nicotine salt formulation Versus two protons, thus resulting in better transfer efficiency. 65 provided herein is “water clear in appearance in order to In addition, the lack of satisfaction of free base nicotine avoid or minimize the formation of tarry residues during the indicates that a second factor may be important. A nicotine Subsequent salt formation steps. US 9,215,895 B2 15 16 Nicotine salt formulations used for e-cigarettes described tion of about 1% (w/w). Certain embodiments provide a nico herein, in Some embodiments, have a nicotine concentration tine salt formulation having a nicotine concentration of about of about 0.5% (w/w) to about 20% (w/w), wherein the con 0.5% (w/w). centration is of nicotine weight to total solution weight, i.e. The formulation further may comprise one or more fla (w/w). In certain embodiments, nicotine salt formulations 5 VOrantS. provided herein have a nicotine concentration of about 1% The suitable acid for the nicotine salt formulation may have (w/w) to about 20% (w/w). In certain embodiments, nicotine a vapor pressure >20 mmHg at 200° C. and is non-corrosive salt formulations provided herein have a nicotine concentra to the electronic cigarette or is non-toxic to humans. In some tion of about 1% (w/w) to about 18% (w/w). In certain embodiments, the suitable acid for nicotine salt formation is embodiments, nicotine Salt formulations provided herein 10 selected from the group consisting of salicylic acid, formic have a nicotine concentration of about 1% (w/w) to about 15% (w/w). In certain embodiments, nicotine salt formula acid, Sorbic acid, acetic acid, benzoic acid, pyruvic acid, tions provided herein have a nicotine concentration of about lauric acid, and levulinic acid. 4% (w/w) to about 12% (w/w). In certain embodiments, nico The suitable acid for the nicotine salt formulation may have tine Salt formulations provided herein have a nicotine con- 15 a vapor pressure of about 20 to 200 mmHg at 200° C. and is centration of about 1% (w/w) to about 18% (w/w), about 3% non-corrosive to the electronic cigarette or is non-toxic to (w/w) to about 15% (w/w), or about 4% (w/w) to about 12% humans. In some embodiments, the Suitable acid for nicotine (w/w). In certain embodiments, nicotine salt formulations salt formation is selected from the group consisting of Sali provided herein have a nicotine concentration of about 0.5% cylic acid, benzoic acid, lauric acid, and levulinic acid. (w/w) to about 10% (w/w). In certain embodiments, nicotine 20 The suitable acid for the nicotine salt formulation may have salt formulations provided herein have a nicotine concentra a melting point <160° C., a boiling point >160° C., at least a tion of about 0.5% (w/w) to about 5% (w/w). In certain 50-degree difference between the melting point and the boil embodiments, nicotine Salt formulations provided herein ing point, and is non-corrosive to the electronic cigarette or is have a nicotine concentration of about 0.5% (w/w) to about non-toxic to humans. In some embodiments, the Suitable acid 4% (w/w). In certain embodiments, nicotine salt formulations 25 for nicotine salt formation has a melting point at least 40 provided herein have a nicotine concentration of about 0.5% degrees lower than the operating temperature of the electronic (w/w) to about 3% (w/w). In certain embodiments, nicotine cigarette, a boiling point no more than 40 degrees lower than salt formulations provided herein have a nicotine concentra the operating temperature of the electronic cigarette, at least tion of about 0.5% (w/w) to about 2% (w/w). In certain a 50-degree difference between the melting point and the embodiments, nicotine salt formulations provided herein 30 boiling point, and is non-corrosive to the electronic cigarette have a nicotine concentration of about 0.5% (w/w) to about 1% (w/w). In certain embodiments, nicotine salt formulations or is non-toxic to humans; wherein the operating temperature provided herein have a nicotine concentration of about 1% is 200°C. In some embodiments, the suitable acid for nicotine (w/w) to about 10% (w/w). In certain embodiments, nicotine salt formation is selected from the group consisting of Sali salt formulations provided herein have a nicotine concentra- 35 cylic acid, Sorbic acid, benzoic acid, pyruvic acid, lauric acid, tion of about 1% (w/w) to about 5% (w/w). In certain embodi and levulinic acid. ments, nicotine salt formulations provided herein have a nico The suitable acid for the nicotine salt formulation does not tine concentration of about 1% (w/w) to about 4% (w/w). In decompose at the operating temperature of the electronic certain embodiments, nicotine salt formulations provided cigarette. In some embodiments, the Suitable acid for nicotine herein have a nicotine concentration of about 1% (w/w) to 40 salt formation does not oxidize at the operating temperature about 3% (w/w). In certain embodiments, nicotine salt for of the electronic cigarette. In some embodiments, the Suitable mulations provided herein have a nicotine concentration of acid for nicotine salt formation does not oxidize at room about 1% (w/w) to about 2% (w/w). In certain embodiments, temperature. In some embodiments, the Suitable acid for nicotine salt formulations provided herein have a nicotine nicotine Salt formation does not provide an unpleasant taste. concentration of about 2% (w/w) to about 10% (w/w). In 45 In some embodiments, the suitable acid for nicotine salt for certain embodiments, nicotine salt formulations provided mation has good solubility in a liquid formulation for use in herein have a nicotine concentration of about 2% (w/w) to an electronic cigarette. about 5% (w/w). In certain embodiments, nicotine salt for Provided herein is an electronic cigarette 2 having a fluid mulations provided herein have a nicotine concentration of storage compartment 4 comprising an embodiment nicotine about 2% (w/w) to about 4% (w/w). Certain embodiments 50 salt formulation of any embodiment described herein within provide a nicotine salt formulation having a nicotine concen the fluid storage compartment described herein. An embodi tration of about 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, ment is shown in FIG. 7. The electronic cigarette 2 of FIG. 7 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, includes a mouth end 6, and a charging end 8. The mouth-end 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 6 includes a mouthpiece 10. The charging end 8 may connect 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 55 to a battery or a charger or both, wherein the battery is within 3.9%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, a body of the electronic cigarette, and the charger is separate 8.0%, 8.5%, 9.0%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, from the battery and couples to the body or the battery to 16%, 17%, 18%. 19%, or 20% (w/w), or more, including any charge the battery. In some embodiments the electronic ciga increments therein. Certain embodiments provide a nicotine rette comprises a rechargeable battery within a body 14 of the salt formulation having a nicotine concentration of about 5% 60 electronic cigarette and the charge end 8 comprises a connec (w/w). Certain embodiments provide a nicotine salt formula tion 12 for charging the rechargeable battery. In some tion having a nicotine concentration of about 4% (w/w). Cer embodiments, the electronic cigarette comprises a cartomizer tain embodiments provide a nicotine salt formulation having that comprises the fluid storage compartment and an atom a nicotine concentration of about 3% (w/w). Certain embodi izer. In some embodiments, the atomizer comprises a heater. ments provide a nicotine Salt formulation having a nicotine 65 In some embodiments the fluid storage compartment 4 is concentration of about 2% (w/w). Certain embodiments pro separable from an atomizer. In some embodiments the fluid vide a nicotine salt formulation having a nicotine concentra storage compartment 4 is replaceable as part of a replaceable US 9,215,895 B2 17 18 cartridge. In some embodiments the fluid storage compart Nicotine Succinate salt formulation was made by adding ment 4 is refillable. In some embodiments, the mouthpiece 10 0.29 g succinic acid to a beaker followed by adding 0.2 is replaceable. g nicotine and 9.51 g PG/VG (3:7) solution to the same Provided herein is a cartomizer 18 for an electronic ciga beaker. The mixture was then Stirred at 90° C. for 60 rette 2 having a fluid storage compartment 4 comprising an 5 minutes until a visually homogenous formulation solu embodiment nicotine salt formulation of any embodiment tion was achieved with no undissolved chemicals. described herein within the fluid storage compartment Nicotine Salicylate salt formulation was made by adding described herein. The cartomizer 18 embodiment of FIG. 8 0.17 g salicylic acid to a beaker followed by adding 0.2 includes a mouth end 6, and a connection end 16. The con g nicotine and 9.63 g PG/VG (3:7) solution to the same nection end 16 in the embodiment of FIG. 8 couples the 10 beaker. The mixture was then Stirred at 90° C. for 60 cartomizer 14 to a body of an electronic cigarette, or to a minutes until a visually homogenous formulation solu battery of the electronic cigarette, or both. The mouth end 6 includes a mouthpiece 10. In some embodiments, the car tion was achieved with no undissolved chemicals. tomizer does not include a mouthpiece, and in Such embodi Nicotine salicylate salt formulation can also be made by ments, the cartomizer can be coupled to a mouthpiece of an 15 adding 0.17 g salicylic acid to a beaker followed by electronic cigarette, or the cartomizer can be coupled to a adding 0.2 g nicotine to the same beaker. The mixture battery or body of an electronic cigarette, while the mouth was stirred at 90° C. for 60 minutes until salicylic acid piece is also coupled to the battery or the body of the elec was completely dissolved and an orange oily mixture tronic cigarette. In some embodiments, the mouthpiece is was formed. The mixture was either cooled to ambient integral with the body of the electronic cigarette. In some conditions or kept at 90° C. when 9.63 g PG/VG (3:7) embodiments, including the embodiment of FIG. 8, the car solution was added. The mixture was then stirred at 90° tomizer 18 comprises the fluid storage compartment 4 and an C. until a visually homogenous formulation solution atomizer (not shown). In some embodiments, the atomizer was achieved with no undissolved chemicals. comprises a heater (not shown) Nicotine free base formulation was made by adding 0.2g 25 nicotine to a beaker followed by adding 9.8 g. PG/VG EXAMPLES (3:7) solution to the same beaker. The mixture was then stirred at ambient conditions for 10 minutes until a visu Example 1 ally homogenous formulation Solution was achieved. For example, in order to make nicotine salt formulations Preparation of Nicotine Salt Formulations 30 with a final nicotine free base equivalent concentration of 3% (w/w), the following procedures were applied to each indi Various nicotine formulations were prepared and added to vidual formulation. a solution of 3:7 ratio by weight of propylene glycol (PG)/ Nicotine benzoate salt formulation: 0.23 g benzoic acid vegetable glycerin (VG), and mixed thoroughly. The was added to a beaker followed by adding 0.3 g nicotine examples shown below were used to make 10g of each of the 35 to the same beaker. The mixture was stirred at 55° C. for formulations. All procedures are scalable. 20 minutes until benzoic acid was completely dissolved For example, in order to make nicotine formulations with a and an orange oily mixture was formed. The mixture was final nicotine free base equivalent concentration of 2% (w/w), cooled down to ambient conditions. 9.47g PG/VG (3:7) the following procedures were applied to each individual Solution was added to the orange nicotine benzoate salt formulation. 40 and the blend was stirred until a visually homogenous Nicotine benzoate salt formulation: 0.15 g benzoic acid formulation Solution was achieved. was added to a beaker followed by adding 0.2 g nicotine Nicotine benzoate salt formulation can also be made by to the same beaker. The mixture was stirred at 55° C. for adding 0.23 g benzoic acid to a beaker followed by 20 minutes until benzoic acid was completely dissolved adding 0.3 g nicotine and 9.47g PG/VG (3:7) solution to and an orange oily mixture was formed. The mixture was 45 the same beaker. The mixture was then stirred at 55° C. cooled down to ambient conditions. 9.65 g PG/VG (3:7) for 20 minutes until a visually homogenous formulation Solution was added to the orange nicotine benzoate salt Solution was achieved with no undissolved chemicals. and the mixture was stirred until a visually homogenous Nicotine citrate salt formulation was made by adding 0.71 formulation solution was achieved. g citric acid to a beaker followed by adding 0.3 g nicotine Nicotine benzoate salt formulation can also be made by 50 and 8.99g PG/VG(3:7) solution to the same beaker. The adding 0.15 g benzoic acid to a beaker followed by mixture was then stirred at 90° C. for 60 minutes until a adding 0.2 g nicotine and 9.65 g PG/VG (3:7) solution to visually homogenous formulation solution was the same beaker. The mixture was then stirred at 55° C. achieved with no undissolved chemicals. for 20 minutes until a visually homogenous formulation Nicotine malate salt formulation was made by adding 0.5g Solution was achieved with no undissolved chemicals. 55 L-malic acid to a beaker followed by adding 0.3 g nico Nicotine citrate salt formulation was made by adding 0.47 tine and 9.2 g PG/VG (3:7) solution to the same beaker. g citric acid to a beaker followed by adding 0.2g nicotine The mixture was then stirred at 90° C. for 60 minutes and 9.33 g PG/VG(3:7) solution to the same beaker. The until a visually homogenous formulation Solution was mixture was then stirred at 90° C. for 60 minutes until a achieved with no undissolved chemicals. visually homogenous formulation solution was 60 Nicotine levulinate salt formulation was made by adding achieved with no undissolved chemicals. melted 0.64 g levulinic acid to a beaker followed by Nicotine malate salt formulation was made by adding 0.33 adding 0.3 g nicotine to the same beaker. The mixture g L-malic acid to a beaker followed by adding 0.2g was stirred at ambient conditions for 10 minutes. Exo nicotine and 9.47 g PG/VG (3:7) solution to the same thermic reaction took place and oily product was pro beaker. The mixture was then Stirred at 90° C. for 60 65 duced. The mixture was allowed to cool down to ambi minutes until a visually homogenous formulation solu ent temperature and 9.06 g PG/VG (3:7) solution was tion was achieved with no undissolved chemicals. added to the same beaker. The mixture was then stirred US 9,215,895 B2 19 20 at ambient conditions for 20 minutes until a visually cooled down to ambient conditions. 9.12g PG/VG (3:7) homogenous formulation Solution was achieved. Solution was added to the orange nicotine benzoate salt Nicotine pyruvate salt formulation was made by adding and the blend was stirred until a visually homogenous 0.33 g pyruvic acid to a beaker followed by adding 0.3g formulation Solution was achieved. nicotine to the same beaker. The mixture was stirred at Nicotine benzoate salt formulation can also be made by ambient conditions for 10 minutes. Exothermic reaction adding 0.38 g benzoic acid to a beaker followed by took place and oily product was produced. The mixture adding 0.5g nicotine and 9.12g PG/VG (3:7) solution to was allowed to cool down to ambient temperature and the same beaker. The mixture was then stirred at 55° C. 9.37 g PG/VG (3:7) solution was added to the same for 20 minutes until a visually homogenous formulation beaker. The mixture was then stirred at ambient condi 10 tions for 20 minutes until a visually homogenous formu Solution was achieved with no undissolved chemicals. lation Solution was achieved. Nicotine malate salt formulation was made by adding 0.83 Nicotine Succinate salt formulation was made by adding g L-malic acid to a beaker followed by adding 0.5 g. nicotine and 8.67 g PG/VG (3:7) solution to the same 0.44 g succinic acid to a beaker followed by adding 0.3 beaker. The mixture was then Stirred at 90° C. for 60 g nicotine and 9.26 g PG/VG (3:7) solution to the same 15 beaker. The mixture was then Stirred at 90° C. for 60 minutes until a visually homogenous formulation solu minutes until a visually homogenous formulation solu tion was achieved with no undissolved chemicals. tion was achieved with no undissolved chemicals. Nicotine levulinate salt formulation was made by adding Nicotine salicylate salt formulation was made by adding melted 1.07 g levulinic acid to a beaker followed by 0.26 g salicylic acid to a beaker followed by adding 0.3 adding 0.5 g nicotine to the same beaker. The mixture g nicotine and 9.44 g PG/VG (3:7) solution to the same was stirred at ambient conditions for 10 minutes. Exo beaker. The mixture was then Stirred at 90° C. for 60 thermic reaction took place and oily product was pro minutes until a visually homogenous formulation solu duced. The mixture was allowed to cool down to ambi tion was achieved with no undissolved chemicals. ent temperature and 8.43 g PG/VG (3:7) solution was Nicotine salicylate salt formulation can also be made by 25 added to the same beaker. The mixture was then stirred adding 0.26 g salicylic acid to a beaker followed by at ambient conditions for 20 minutes until a visually adding 0.3 g nicotine to the same beaker. The mixture homogenous formulation solution was achieved. was stirred at 90° C. for 60 minutes until salicylic acid Nicotine pyruvate salt formulation was made by adding was completely dissolved and an orange oily mixture 0.54 g pyruvic acid to a beaker followed by adding 0.5g was formed. The mixture was either cooled to ambient 30 nicotine to the same beaker. The mixture was stirred at conditions or kept at 90° C. when 9.44 g PG/VG (3:7) ambient conditions for 10 minutes. Exothermic reaction solution was added. The blend was then stirred at 90 C took place and oily product was produced. The mixture until a visually homogenous formulation Solution was was allowed to cool down to ambient temperature and achieved with no undissolved chemicals. 8.96 g PG/VG (3:7) solution was added to the same Nicotine free base formulation was made by adding 0.3 g 35 beaker. The mixture was then stirred at ambient condi nicotine to a beaker followed by adding 9.7 g PG/VG tions for 20 minutes until a visually homogenous formu (3:7) solution to the same beaker. The mixture was then lation solution was achieved. stirred at ambient conditions for 10 minutes until a visu Nicotine Succinate salt formulation was made by adding ally homogenous formulation solution was achieved. 0.73 g succinic acid to a beaker followed by adding 0.5 For example, in order to make nicotine salt formulations 40 g nicotine and 8.77 g PG/VG (3:7) solution to the same with a final nicotine free base equivalent concentration of 4% beaker. The mixture was then Stirred at 90° C. for 60 (w/w), the following procedures were applied to each indi minutes until a visually homogenous formulation solu vidual formulation. tion was achieved with no undissolved chemicals. Nicotine benzoate salt formulation: 0.3 g benzoic acid was Nicotine Salicylate salt formulation was made by adding added to a beaker followed by adding 0.4 g nicotine to 45 0.43 g salicylic acid to a beaker followed by adding 0.5 the same beaker. The mixture was stirred at 55° C. for 20 g nicotine and 9.07 g. PG/VG (3:7) solution to the same minutes until benzoic acid was completely dissolved beaker. The mixture was then Stirred at 90° C. for 60 and an orange oily mixture was formed. The mixture was minutes until a visually homogenous formulation solu cooled down to ambient conditions. 9.7 g PG/VG (3:7) tion was achieved with no undissolved chemicals. Solution was added to the orange nicotine benzoate salt 50 Nicotine salicylate salt formulation can also be made by and the blend was stirred until a visually homogenous adding 0.43 g salicylic acid to a beaker followed by formulation solution was achieved. adding 0.5 g nicotine to the same beaker. The mixture Nicotine benzoate salt formulation can also be made by was stirred at 90° C. for 60 minutes until salicylic acid adding 0.3 g benzoic acid to a beaker followed by adding was completely dissolved and an orange oily mixture 0.4 g nicotine and 9.7 g PG/VG (3:7) solution to the 55 was formed. The mixture was either cooled to ambient same beaker. The mixture was then stirred at 55° C. for conditions or kept at 90 C when 9.07 g. PG/VG (3:7) 20 minutes until a visually homogenous formulation solution was added. The blend was then stirred at 90° C. Solution was achieved with no undissolved chemicals. until a visually homogenous formulation Solution was For example, in order to make nicotine salt formulations achieved with no undissolved chemicals. with a final nicotine free base equivalent concentration 60 Nicotine free base formulation was made by adding 0.5g of 5% (w/w), the following procedures were applied to nicotine to a beaker followed by adding 9.5 g PG/VG each individual formulation. (3:7) solution to the same beaker. The mixture was then Nicotine benzoate salt formulation: 0.38 g benzoic acid stirred at ambient conditions for 10 minutes until a visu was added to a beaker followed by adding 0.5g nicotine ally homogenous formulation Solution was achieved. to the same beaker. The mixture was stirred at 55° C. for 65 Various formulations comprising different nicotine salts 20 minutes until benzoic acid was completely dissolved can be prepared similarly, or different concentrations of the and an orange oily mixture was formed. The mixture was above-noted nicotine formulations or other nicotine salt for US 9,215,895 B2 21 22 mulations can be prepared as one of skill in the art would nicotine by weight. In addition, the nicotine salts (e.g., nico know to do upon reading the disclosure herein. tine benzoate and nicotine pyruvate) prepared from the acids Various formulations comprising two or more nicotine having calculated vapor pressures between 20-200 mmHg at salts can be prepared similarly in a solution of 3:7 ratio of 200°C. (benzoic acid (171.66 mmHg), with the exception of propylene glycol (PG)/vegetable glycerin (VG). For 5 pyruvic acid (having a boiling point of 165 C), respectively) example, 0.43 g (2.5% w/w nicotine) of nicotine levulinate cause a faster rise in heart rate than the rest. The nicotine salts salt and 0.34 g (2.5% w/w nicotine) of nicotine acetate salt are (e.g., nicotine levulinate, nicotine benzoate, and nicotine Sali added to 9.23 g of PG/VG solution, to achieve a 5% w/w cylate) prepared from the acids (benzoic acid, levulinic acid nicotine formulation. and salicylic acid, respectively) also cause a more significant Also provided is another exemplary formulation. For 10 heart rate increase. Thus, other suitable nicotine salts formed example, 0.23 g (1.33% w/w nicotine) of nicotine benzoate by the acids with the similar vapor pressure and/or similar salt (molar ratio 1:1 nicotine/benzoic acid), 0.25 g (1.33% boiling point may be used in accordance with the practice of W/w nicotine) of nicotine salicylate salt (molar ratio 1:1 nico the present invention. This experience of increased heart rate tine/salicylic acid) and 0.28 g (1.34% w/w nicotine) of nico theoretically approaching or theoretically comparable to that tine pyruvate salt (molar ratio 1:2 nicotine/pyruvic acid) are 15 added to 9.25 g of PG/VG solution, to achieve a 5% w/w of a traditional burned cigarette has not been demonstrated or nicotine formulation. identified in other electronic cigarette devices. Nor has it been demonstrated or identified in low temperature tobacco vapor Example 2 ization devices (electronic cigarettes) that do not burn the tobacco, even when a nicotine salt was used (a solution of Heart Rate Study of Nicotine Solutions Via 20% (w/w) or more of nicotine salt) as an additive to the e-Cigarette tobacco. Thus the results from this experiment are Surprising and unexpected. Exemplary formulations of nicotine levulinate, nicotine benzoate, nicotine Succinate, nicotine Salicylate, nicotine 25 Example 3 malate, nicotine pyruvate, nicotine citrate, nicotine freebase, and a control of propylene glycol were prepared as noted in Satisfaction Study of Nicotine Salt Solution Via Example 1 in 3% w/w solutions and were administered in the e-Cigarette same fashion by an electronic cigarette to the same human subject. About 0.5 mL of each solution was loaded into an 30 In addition to the heart rate study shown in Example 2, “eRoll' cartridge atomizer (joyetech.com) to be used in the nicotine formulations (using 3% W/w nicotine formulations study. The atomizer was then attached to an “eRoll' e-ciga as described in Example 1) were used to conduct a satisfac rette (same manufacturer). The operating temperature was tion study in a single test participant. The test participant, an from about 150° C. to about 250° C., or from about 180° C. to e-cigarette and/or traditional cigarette user, was required to about 220° C. 35 Heart rate measurements were taken for 6 minutes; from 1 have no nicotine intake for at least 12 hours before the test. minute before start of puffing, for 3 minutes during puffing, The participant took 10 puffs using an e-cigarette (same as and continuing until 2 minutes after end of puffing. The test used in Example 2) over 3 minutes in each case, and then was participant took 10 puffs over 3 minutes in each case. The asked to rate the level of physical and emotional satisfaction base heart rate was the average heart rate over the first 1 40 he or she felt on a scale of 0-10, with 0 being no physical or minute before start of puffing. Heart rate after puffing started emotional satisfaction. The results indicated that the least was averaged over 20-second intervals. Puffing (inhalation) satisfying compound was the nicotine free base. Nicotine occurred every 20 seconds for a total of 3 minutes. Normal benzoate, nicotine salicylate, and nicotine Succinate all per ized heart rate was defined as the ratio between individual formed well, followed by nicotine pyruvate, nicotine citrate, heart rate data point and the base heart rate. Final results were 45 and nicotine pyruvate. presented as normalized heart rate, shown for the first 4 min Based on the Satisfaction Study, the nicotine salts formu utes in FIG. 1. lations with acids having vapor pressure ranges between >20 FIG. 1 summarizes results from heart rate measurements mmHg (a 200° C., or 20-200 mmHg (a 200° C., or 100-300 taken for a variety of nicotine salt formulations. For ease of mmHg (a) 200° C. provide more satisfaction than the rest reference in reviewing FIG. 1, at the 180-second timepoint, 50 (except the pyruvic acid which has boiling point of 165° C.). from top to bottom (highest normalized heart rate to lowest For reference, it has been determined that salicylic acid has a normalized heart rate), the nicotine formulations are as fol vapor pressure of about 135.7 mmHg (a) 200°C., benzoic acid lows: nicotine salicylate formulation, nicotine malate formu has a vapor pressure of about 171.7 mmHg (a 200°C., lauric lation, nicotine levulinate formulation (nearly identical to acid has a vapor pressure of about 38 mmHg (a 200°C., and nicotine malate formulation at 180 seconds, thus, as a second 55 levulinic acid has a vapor pressure of about 149 mmHg (a) reference point: the nicotine malate formulation curve is 2000 C. lower than the nicotine levulinate formulation curve at the 160-second time point), nicotine pyruvate formulation, nico Example 4 tine benzoate formulation, nicotine citrate formulation, nico tine Succinate formulation, and nicotine free base formula 60 Test Formulation 1 (TF1) tion. The bottom curve (lowest normalized heart rate) at the 180-second timepoint is associated with the placebo (100% A Solution of nicotine levulinate in glycerol comprising propylene glycol). The test formulations comprising a nico nicotine salt used: 1.26 g (12.6% w/w) of 1:3 nicotine levuli tine salt cause a faster and more significant rise in heart rate nate 8.74 g (87.4% w/w) of glycerol Total weight 10.0 g. than the placebo. The test formulations comprising a nicotine 65 Neat nicotine levulinate was added to the glycerol, and salt also cause faster and more significant rise when compared mixed thoroughly. L-Nicotine has a molar mass of 162.2g, with a nicotine freebase formulation with the same amount of and levulinic acid molar mass is 116.1 g. In a 1:3 molar ratio, US 9,215,895 B2 23 24 the percentage of nicotine in nicotine levulinate by weight is a difference between boiling point and melting point of at given by: 162.2 g/(162.2g+(3x116.1 g))=31.8% (w/w). least 50°C., and a boiling point greater than 160°C., and a melting point less than 160°C., Example 5 a difference between boiling point and melting point of at least 50° C., and a boiling point at most 40°C. less than operating temperature, and a melting point at least 40° Test Formulation 2 (TF2) C. lower than operating temperature, or a combination thereof produce one or more of the follow A solution of free base nicotine in glycerol comprising 0.40 ing effects: g (4.00% w/w) of L-nicotine was dissolved in 9.60 g (96.0% T Time to maximum blood concentration: Based on W/w) of glycerol and mixed thoroughly. 10 the results established herein, a user of an e-cigarette com prising the nicotine salt formulation will experience a com Example 6 parable rate of physical and emotional satisfaction from using a formulation comprising a mixture of nicotine salts prepared Heart Rate Study of Nicotine Solutions Via with an appropriate acid at least 1.2x to 3x faster than using a e-Cigarette 15 formulation comprising a freebase nicotine. As illustrated in FIG. 1: Nicotine from a nicotine salts formulation appears to Both formulations (TF1 and TF2) were administered in the generate a heartbeat that is nearly 1.2 times that of a normal same fashion by an electronic cigarette to the same human heart rate for an individual approximately 40 seconds after the subject: about 0.6 mL of each solution was loaded into “eGo commencement of puffing; whereas the nicotine from a nico C” cartridge atomizer (joyetech.com). The atomizer was then tine freebase formulation appears to generate a heartbeat that attached to an “eVice-cigarette (same manufacturer). This is nearly 1.2 times that of a normal heart rate for an individual model of e-cigarette allows for adjustable Voltage, and there approximately 110 seconds after the commencement of puff fore wattage, through the atomizer. The operating tempera ing; a 2.75x difference in time to achieve a comparable initial ture of the e-cigarette is from about 150° C. to about 250° C. satisfaction level. or from about 180° C. to about 220° C. 25 Again this would not be inconsistent with the data from The atomizer in both cases has resistance 2.4 ohms, and the FIG. 2, where the data illustrated that at approximately 120 e-cigarette was set to 4.24V, resulting in 7.49 W of power. seconds (2 minutes), the heart rate of test participants reached a maximum of 105-110 bpm with either a regular cigarette or (P=V2/R) a nicotine salt formulation (TF1); whereas those same par Heart rate was measured in a 30-second interval for ten ticipants heart rates only reached a maximum of approxi minutes from start of puffing. Test participants took 10 puffs 30 mately 86 bpm at approximately 7 minutes with a nicotine over 3 minutes in each case (solid line (2" highest peak): freebase formulation (TF2); also a difference in effect of 1.2 cigarette, dark dotted line (highest peak): test formulation 1 times greater with nicotine salts (and regular cigarettes) ver (TF1—nicotine salt formulation), light dotted line: test for SuS freebase nicotine. mulation 2 (TF2—nicotine formulation). Comparison Further, when considering peak satisfaction levels between cigarette, TF1, and TF2 is shown in FIG. 2. 35 (achieved at approximately 120 seconds from the initiation of It is clearly shown in FIG. 2 that the test formulation with puffing (time-0) and looking at the slope of the line for a nicotine levulinate (TF1) causes a faster rise in heart rate than normalized heart rate, the approximate slope of those nicotine just nicotine (TF2). Also, TF1 more closely resembles the rate salt formulations that exceeded the freebase nicotine formu of increase for a cigarette. Other salts were tried and also lation range between 0.0054 hr/sec and 0.0025 hr/sec. By found to increase heart rate relative to a pure nicotine Solu 40 comparison, the slope of the line for the freebase nicotine tion. Thus, other suitable nicotine salts that cause the similar formulation is about 0.002. This would suggest that the con effect may be used in accordance with the practice of the centration of available nicotine will be delivered to the user at present invention. For example, other keto acids (alpha-keto a rate that is between 1.25 and 2.7 times faster than a freebase acids, beta-keto acids, gamma-keto acids, and the like) Such formulation. as pyruvic acid, oxaloacetic acid, acetoacetic acid, and the 45 In another measure of performance; C-Maximum blood nicotine concentration; it is anticipated that similar like. This experience of increased heart rate comparable to rates of increase will be measured in blood nicotine concen that of a traditional burned cigarette has not been demon tration, as those illustrated above. That is, it was anticipated strated or identified in other electronic cigarette devices, nor based on the findings herein, and unexpected based on the art has it been demonstrated or identified in low temperature known to date, that there would be comparable C between tobacco vaporization devices that do not burn the tobacco, 50 the common cigarette and certain nicotine salt formulations, even when a nicotine salt was used (a solution of 20% (W/W) but with a lower C in a freebase nicotine Solution. or more of nicotine salt) as an additive to the tobacco. Thus the Similarly, anticipated based on the findings herein, and results from this experiment are Surprising and unexpected. unexpected based on the art known to date, that certain nico In addition, the data appears to correlate well with the tine salt formulations would have higher rate of nicotine previous findings shown in FIG. 2. 55 uptake levels in the blood at early time periods. Indeed, As previously noted in the Satisfaction Study, the nicotine Example 8 presents data for multiple salt formulations con salts formulations with acids having vapor pressures between sistent with these predictions which were made based on the 20-300 mmHg (a 200° C. provide more satisfaction than the findings and tests noted herein, and unexpected compared to rest, with the exception of the nicotine salt formulation made the art available to date. with pyruvic acid, which has a boiling point of 165° C., as 60 noted in FIG. 3. Based on the findings herein, it was antici Example 7 pated that these nicotine salt formulations having either: a Vapor Pressure between 20-300 mmHg (a) 200°C., Heart Rate Study of Nicotine Solutions Via a Vapor Pressure >20 mmHg (a) 200° C., e-Cigarette a difference between boiling point and melting point of at 65 least 50°C., and a boiling point greater than 160°C., and Exemplary formulations of nicotine levulinate, nicotine a melting point less than 160° C. benzoate, nicotine Succinate, nicotine salicylate, nicotine US 9,215,895 B2 25 26 malate, nicotine pyruvate, nicotine citrate, nicotine Sorbate, Pharmacokinetic profiles of the blood plasma testing are nicotine laurate, nicotine freebase, and a control of propylene shown in FIG. 4; showing blood nicotine concentrations (ng/ glycol are prepared as noted in Example 1 and are adminis mL) over time after the first puff (inhalation) of the aerosol tered in the same fashion by an electronic cigarette to the from the e-cigarette or the smoke of the Pall Mall. Ten puffs same human subject. About 0.5 mL of each solution is loaded were taken at 30 sec intervals starting at time=0 and continu into an “eRoll cartridge atomizer (joyetech.com) to be used ing for 4.5 minutes. For ease of reference and review of FIG. in the study. The atomizer is then attached to an “eRoll 4, at the 5-minute timepoint, the curves on the graph show e-cigarette (same manufacturer). The operating temperature from top to bottom (highest average blood nicotine concen of the e-cigarette is from about 150° C. to about 250° C., or tration to lowest average blood nicotine concentration) are from about 180° C. to about 220° C. 10 4% benzoate, 2% succinate, 2% salicylate, 2% citrate, Pall Heart rate measurements are taken for 6 minutes; from 1 Mall cigarette, 2% benzoate, 2% malate, and 2% free base minute before start of puffing, for 3 minutes during puffing, blend. Although noted as highest to lowest at this time point, and continuing until 2 minutes after end of puffing. The test this is not to say that there is a statistically significant differ participant takes 10 puffs over 3 minutes in each case. The ence between any of the salt formulations, or between any of 15 the salt formulations and the Pall Mall cigarette. However, it base heart rate is the average heart rate over the first 1 minute is possible there may be a statistically significant difference before start of puffing. Heart rate after puffing started is between the C of particular Saltformulations, and it is also averaged over 20-second intervals. Normalized heart rate is likely based on the data shown in FIG. 4 and in other studies defined as the ratio between individual heart rate data point herein that the freebase formulation is statistically different and the base heart rate. Final results are presented as normal from salt formulations and/or the Pall Mall with respect to ized heart rate. C, since it appears lower than others tested at several time Example 8 points. One of skill in the art, upon review of the disclosure herein could properly power a test to determine actual statis Blood Plasma Testing tically-based differences between one or more formulations 25 and the cigarette, or between the formulations themselves in Blood plasma testing was conducted on three Subjects an e-cigarette. For ease of reference Tables 1 & 2 present the (n-3). Eight test articles were used in this study: one refer amount of nicotine detected (as an average of all users) for ence cigarette and seven blends used in an e-cigarette device each formulation and the Pall Mall, presented in ng/mL, along having an operating temperature of the e-cigarette from about with C and T and AUC. Data from these tables, along 150° C. to about 250° C., or from about 180° C. to about 220° 30 with the raw data therefore, was used to generate FIGS. 4, 5, C. The reference cigarette was Pall Mall (New Zealand). and 6. Seven blends were tested in the e-cigarette: 2% free base, 2% benzoate, 4% benzoate, 2% citrate, 2% malate, 2% salicylate, TABLE 1 and 2% succinate. Except for 2% succinate (n=1), all other 35 2% 2% 4% blends have n=3. The seven blends were liquid formulations Time Pall Mall Freebase Benzoate Benzoate prepared as described in Example 1. -2 O46 O.O3 O.09 O.OS The concentration of nicotine in each of the formulations O -0.46 -O.O3 -O.09 -0.05 was confirmed using UV spectrophotometer (Cary 60, manu 1.5 1.54 O.08 5.67 6.02 factured by Agilent). The sample solutions for UV analysis 3 9.98 1.19 8.60 11.47 40 5 11.65 1.70 11.44 15.06 were made by dissolving 20 mg of each of the formulations in 7.5 11.34 3.09 6.43 12.12 20 mL 0.3% HCl in water. The sample solutions were then 10 9.24 3.42 S.O.3 11.08 scanned in UV spectrophotometer and the characteristic nico 12.5 8.85 3.35 4.68 10.10 tine peak at 259 nm was used to quantify nicotine in the 15 840 2.81 4.47 8.57 sample against a standard solution of 19.8 ug/mL nicotine in 30 5.51 1.74 2.72 5.56 45 60 3.39 0.79 1.19 3.60 the same diluent. The standard solution was prepared by first T (min) 5.17 1O.OO 6.67 5.83 dissolving 19.8 mg nicotine in 10 mL 0.3% HCl in water C (ng/mL) 11.65 3.42 11.44 15.06 followed by a 1:100 dilution with 0.3% HCl in water. Nico AUC (ng * min/mL) 367.5 106.2 2O7.8 4002 tine concentrations reported for all formulations were within the range of 95%-105% of the claimed concentrations All subjects were able to consume 30-55 mg of the liquid 50 formulation of each tested blend using the e-cigarette. TABLE 2 Literature results: C. Bullen et al, Tobacco Control 2010, 296 2% 2% 296 19:98-103 Cigarette (5 min adlib. n=9): T =14.3 Time Citrate Malate Salicylate Succinate (8.8-19.9), C = 13.4 (6.5-20.3) 1.4% E-cig (5 min adlib, 55 -2 O.O6 -0.17 -0.19 -0.06 n=8): T =19.6 (4.9-34.2), C =1.3 (0.0-2.6) Nicorette O -0.06 O.17 O.19 O.O6 Inhalator (20 mg/20 min, n=10): T=32.0 (18.7-45.3), 1.5 4.8O 1.09 6.14 2.10 3 8.33 5.30 12.04 10.81 C=2.1 (1.0-3.1) 5 12.09 10.02 13:46 13.81 Estimated C of 2% nicotine blends: 7.5 6.93 5.93 S.21 5.15 10 6.O1 4.85 4.60 S.18 C=Mass consumed*Strength Bioavailability/(Vol 60 12.5 S.34 4.17 3.83 4.17 of Distribution* Body Weight)=40 mg2%*80%/ 15 4.72 3.79 3.52 3.41 (2.6 L/kg 75 kg)=3.3 ng/mL 30 3.40 1.56 2.19 2.01 60 1.70 O46 0.55 1.00 Estimated C of 4% nicotine blends: T (min) 5.83 S.OO 4.33 S.OO C (ng/mL) 12.09 10.02 13:46 13.81 C=Mass consumed Strength Bioavailability (Vol 65 AUC (ng * min/mL) 238.0 146.1 1829 179.5 of Distribution* Body Weight)=40 mg-4%*80%/ (2.6 L/kg 75 kg)=6.6 ng/mL US 9,215,895 B2 27 28 Comparison of T and C of the seven blends and ence cigarette and ten blends delivered to a user in an e-ciga reference cigarette are shown in FIG. 5. Comparison of C. rette as an aerosol. The reference cigarette is Pall Mall (New and AUC of the seven blends and reference cigarette are Zealand). The operating temperature of the e-cigarette is from shown in FIG. 6. Due to the time limit of the wash-period, about 150° C. to about 250° C., or from about 180°C. to about baseline blood nicotine concentration (at t=-2 and t=0 min) was higher for samples consumed at a later time on the test 220°C. Ten blends are tested: 2% free base, 2% benzoate, 2% day. The data in FIGS. 4-6 show corrected blood nicotine sorbate, 2% pyruvate, 2% laurate, 2% levulinate, 2% citrate, concentration values (i.e. apparent blood nicotine concentra 2% malate, 2% salicylate, and 2% succinate. The ten blends tion at each time point minus baseline nicotine concentration are liquid formulations prepared according to protocols simi of the same sample). lar to that described infra and in Example 1. Rates of nicotine uptake in the blood of the users of each 10 All subjects are to consume 30-55 mg of the liquid formu sample within the first 90 seconds are shown in Table 3. lation of each tested blend. Ten puffs are to be taken at 30 sec intervals starting at time 0 and continuing for 4.5 minutes. TABLE 3 Blood plasma testing is to occur for at least 60 minutes from the first puff (t=0). Pharmacokinetic data (e.g., C. T., Sample Rate of nicotine uptake (ng/mL/min) 15 AUC) for nicotine in the plasma of users are obtained at 2% Salicylate 4.09 various time periods during those 60 minutes, along with 2% Benzoate 3.78 rates of nicotine absorption within the first 90 seconds for 2% Citrate 3.20 each test article. 2% Succinate 140 Pall Mall (reference) 1.03 Example 11 2% Malate 0.73 2% Freebase O.OS 4% Benzoate 4.01 Blood Plasma Testing Although the T and C values are comparable Blood plasma testing is conducted on twenty-four Subjects between the tested blends and the reference cigarette (with the 25 (n=24). Twenty-one test articles are used in this study: one exception of the 2% free base blend), the rates of nicotine reference cigarette and twenty blends delivered to a user in an absorption within the first 90 seconds differed among the test e-cigarette as an aerosol. The reference cigarette is Pall Mall articles. In particular, four blends (2% salicylate, 2% ben (New Zealand). The operating temperature of the e-cigarette Zoate, 4% benzoate, and 2% citrate) showed markedly higher is from about 150° C. to about 250° C., or from about 180° C. rates of absorption within the first 90 seconds compared to the 30 to about 220°C. Twenty blends are tested: 2% free base, 4% other blends and with the reference cigarette. These four free base, 2% benzoate, 4% benzoate, 2% sorbate, 4% sor blends contain salts (salicylate, benzoate, and citrate) which bate, 2% pyruvate, 4% pyruvate, 2% laurate, 4% laurate, 2% performed well in the Satisfaction Study of Example 3. More levulinate, 4% levulinate, 2% citrate, 4% citrate, 2% malate, over, 2% benzoate and 4% benzoate had comparable rates of 4% malate, 2% salicylate, 4% salicylate, 2% succinate, and absorption, Suggesting that a lower concentration of nicotinic 35 4% succinate. The twenty blends are liquid formulations pre salt may not adversely impact the rate of absorption. pared according to protocols similar to that described infra and in Example 1. Example 9 All subjects are to consume 30-55 mg of the liquid formu lation of each tested blend. Ten puffs are to be taken at 30 sec Blood Plasma Testing 40 intervals starting at time 0 and continuing for 4.5 minutes. Blood plasma testing is conducted on 24 Subjects (n=24). Blood plasma testing is to occur for at least 60 minutes from Eight test articles are used in this study: one reference ciga the first puff (t=0). Pharmacokinetic data (e.g., C. T., rette and seven blends delivered to a user in an e-cigarette as AUC) for nicotine in the plasma of users are obtained at an aerosol. The operating temperature of the e-cigarette is various time periods during those 60 minutes, along with from about 150° C. to about 250° C., or from about 180° C. to 45 rates of nicotine absorption within the first 90 seconds for about 220° C. The reference cigarette is Pall Mall (New each test article. Zealand). Seven blends are tested: 2% free base, 2% ben Zoate, 4% benzoate, 2% citrate, 2% malate, 2% salicylate, and Example 12 2% succinate. The seven blends are liquid formulations pre pared according to protocols similar to that described infra 50 Blood Plasma Testing and in Example 1. All subjects are to consume 30-55 mg of the liquid formu Blood plasma testing is conducted on twenty-four Subjects lation of each tested blend. Ten puffs are to be taken at 30 sec (n=24). Twenty-one test articles are used in this study: one intervals starting at time 0 and continuing for 4.5 minutes. reference cigarette and twenty blends delivered to a user in an Blood plasma testing is to occur for at least 60 minutes from 55 e-cigarette as an aerosol. The reference cigarette is Pall Mall the first puff (t=0) Pharmacokinetic data (e.g., C. T., (New Zealand). The operating temperature of the e-cigarette AUC) for nicotine in the plasma of users are obtained at is from about 150° C. to about 250° C., or from about 180° C. various time periods during those 60 minutes, along with to about 220°C. Twenty blends are tested: 2% free base, 1% rates of nicotine absorption within the first 90 seconds for free base, 2% benzoate, 1% benzoate, 2% sorbate, 1% sor each test article. 60 bate, 2% pyruvate, 1% pyruvate, 2% laurate, 1% laurate, 2% levulinate, 1% levulinate, 2% citrate, 1% citrate, 2% malate, Example 10 1% malate, 2% salicylate, 1% salicylate, 2% succinate, and 1% succinate. The twenty blends are liquid formulations pre Blood Plasma Testing pared according to protocols similar to that described infra 65 and in Example 1. Blood plasma testing is conducted on twenty-four Subjects All subjects are to consume 30-55 mg of the liquid formu (n=24). Eleven test articles are used in this study: one refer lation of each tested blend. Ten puffs are to be taken at 30 sec US 9,215,895 B2 29 30 intervals starting at time 0 and continuing for 4.5 minutes. 14. The method any one of embodiments 1-10, wherein the Blood plasma testing is to occur for at least 60 minutes from aerosol comprises condensate of freebase nicotine and con the first puff (t=0). Pharmacokinetic data (e.g., CT densate of the acid. AUC) for nicotine in the plasma of users are obtained at 15. The method any one of embodiments 1-14, wherein the various time periods during those 60 minutes, along with 5 aerosol comprises condensate in particle sizes from about 0.1 rates of nicotine absorption within the first 90 seconds for microns to about 5 microns. each test article. 16. The method any one of embodiments 1-14, wherein the Further understanding may be gained through contempla aerosol comprises condensate in particle sizes from about 0.1 tion of the numbered embodiments below. microns to about 1 or 2 microns. 1. A method of delivering nicotine to a user comprising 10 17. The method any one of embodiments 1-14, wherein the operating an electronic cigarette to a user wherein the elec aerosol comprises condensate in particle sizes from about 0.1 tronic cigarette comprises a nicotine Salt formulation com microns to about 0.7 microns. prising a nicotine salt in a biologically acceptable liquid car 18. The method any one of embodiments 1-14, wherein the rier wherein an acid used to form said nicotine salt is 15 aerosol comprises condensate in particle sizes from about 0.3 characterized by vapor pressure >20 mmHg at 200°C., and microns to about 0.4 microns. inhaling an aerosol generated from the nicotine salt formula 19. The method any one of embodiments 1-18, wherein the tion heated by the electronic cigarette. acid is a carboxylic acid. 2. A method of delivering nicotine to a user comprising 20. The method of any one of embodiments 1-18, wherein operating an electronic cigarette to a user wherein the elec the acid used to form said nicotine salt is an organic acid. tronic cigarette comprises a nicotine Salt formulation com 21. The method of embodiment 20, wherein the organic prising a nicotine salt in a biologically acceptable liquid car acid is monocarboxylic acid, aromatic acid, or keto acid. rier wherein an acid used to form said nicotine salt is 22. The method of embodiment 20, wherein the organic characterized by vapor pressure of about 20 to 200 mmHg at acid is formic acid, acetic acid, propionic acid, butyric acid, 200°C., and inhaling an aerosol generated from the nicotine 25 Valeric acid, caproic acid, caprylic acid, capric acid, citric salt formulation heated by the electronic cigarette. acid, lauric acid, myristic acid, palmitic acid, Stearic acid, 3. A method of delivering nicotine to a user comprising oleic acid, linoleic acid, linolenic acid, phenylacetic acid, operating an electronic cigarette wherein the electronic ciga benzoic acid, pyruvic acid, levulinic acid, tartaric acid, lactic rette comprises a nicotine salt formulation comprising a nico acid, malonic acid. Succinic acid, fumaric acid, finnaric acid, tine Salt in a biologically acceptable liquid carrier wherein an 30 gluconic acid, saccharic acid, Salicylic acid, Sorbic acid, mal onic acid, or malic acid. acid used to form said nicotine salt is further characterized by 23. The method of any one of embodiments 1-18, wherein a melting point<160°C., a boiling point >160°C., and at least the acid used to form the nicotine salt is salicylic acid. a 50-degree difference between the melting point and the 24. The method of any one of embodiments 1-18, wherein boiling point, and inhaling an aerosol generated from the 35 the acid used to form the nicotine salt is benzoic acid. nicotine salt formulation heated by the electronic cigarette. 25. The method of any one of embodiments 1-18, wherein 4. A method of delivering nicotine to a user comprising the acid used to form the nicotine salt is pyruvic acid. providing an electronic cigarette to a user wherein the elec 26. The method of any one of embodiments 1-18, wherein tronic cigarette comprises a nicotine Salt formulation com the acid used to form the nicotine salt is sorbic acid. prising a nicotine salt in a biologically acceptable liquid car 40 27. The method of any one of embodiments 1-18, wherein rier wherein an acid used to form said nicotine salt is further the acid used to form the nicotine salt is lauric acid. characterized by a melting point at least 40 degrees lower than 28. The method of any one of embodiments 1-18, wherein an operating temperature of the electronic cigarette, a boiling the acid used to form the nicotine salt is levulinic acid. point no more than 40 degrees lower than the operating tem 29. The method of any one of embodiments 1-18, wherein perature of the electronic cigarette, and at least a 50-degree 45 said nicotine salt comprises nicotine pyruvate. difference between the melting point and the boiling point, 30. The method of any one of embodiments 1-18, wherein and inhaling an aerosol generated from the nicotine salt for said nicotine salt comprises nicotine Salicylate. mulation heated by the electronic cigarette. 31. The method of any one of embodiments 1-18, wherein 5. The method of any one of embodiments 1-3, wherein an said nicotine salt comprises nicotine Sorbate. operating temperature is from 150° C. to 250° C. 50 32. The method of any one of embodiments 1-18, wherein 6. The method of any one of embodiments 1-3, wherein an said nicotine salt comprises nicotine laurate. operating temperature is from 180°C. to 220°C. 33. The method of any one of embodiments 1-18, wherein 7. The method any one of embodiments 1-3, wherein an said nicotine salt comprises nicotine levulinate. operating temperature is about 200° C. 34. The method of any one of embodiments 1-18, wherein 8. The method of embodiment 4, wherein the operating 55 said nicotine salt comprises nicotine benzoate. temperature is from 150° C. to 250° C. 35. The method of any one of embodiments 1-34, wherein 9. The method of embodiment 4, wherein the operating the liquid carrier comprises glycerol, propylene glycol, trim temperature is from 180° C. to 220° C. ethylene glycol, water, ethanol or combinations thereof. 10. The method of embodiment 4, wherein the operating 36. The method of any one of embodiments 1-34, wherein temperature is about 200°C. 60 the liquid carrier comprises propylene glycol and vegetable 11. The method any one of embodiments 1-10, wherein the glycerin. aerosol comprises condensate of the nicotine salt. 37. The method of any one of embodiments 1-34, wherein 12. The method any one of embodiments 1-10, wherein the the liquid carrier comprises 20% to 50% of propylene glycol aerosol comprises condensate of freebase nicotine. and 80% to 50% of vegetable glycerin. 13. The method any one of embodiments 1-10, wherein the 65 38. The method of any one of embodiments 1-34, wherein aerosol comprises condensate of freebase nicotine and con the liquid carrier comprises 30% propylene glycol and 70% densate of the carrier. Vegetable glycerin. US 9,215,895 B2 31 32 39. The method of any one of embodiments 1-38, wherein 59. The method of embodiment 54, wherein the nicotine the nicotine salt is in an amount that forms about 0.5% to salt formulation comprises a nicotine Salt in a biologically about 20% nicotine in the inhalable aerosol. acceptable liquid carrier wherein an acid used to form said 40. The method of any one of embodiments 1-38, wherein nicotine salt is characterized by vapor pressure of about 20 to the nicotine salt is in an amount that forms about 1% to about 200 mmHg at 200° C. 20% nicotine in the inhalable aerosol. 60. The method of embodiment 54, wherein the nicotine 41. The method of any one of embodiments 1-40, wherein salt formulation comprises a nicotine Salt in a biologically the liquid formulation has a nicotine concentration of about acceptable liquid carrier wherein an acid used to form said 1% (w/w) to about 25% (w/w). nicotine salt is further characterized by a melting point <160° 42. The method of any one of embodiments 1-40, wherein 10 C., a boiling point >160° C., and at least a 50-degree differ the liquid formulation has a nicotine concentration of about ence between the melting point and the boiling point. 1% (w/w) to about 20% (w/w). 61. The method of any one of embodiments 57-60, wherein 43. The method of any one of embodiments 1-40, wherein the heating of the formulation is at a temperature from 150° C. the liquid formulation has a nicotine concentration of about to 250° C. 1% (w/w) to about 18% (w/w). 15 62. The method of any one of embodiments 57-60, wherein 44. The method of any one of embodiments 1-40, wherein the heating of the formulation is at a temperature from 180°C. the liquid formulation has a nicotine concentration of about to 220° C. 1% (w/w) to about 15% (w/w). 63. The method of any one of embodiments 57-60, wherein 45. The method of any one of embodiments 1-40, wherein the heating of the formulation is at a temperature of about the liquid formulation has a nicotine concentration of about 2000 C. 4% (w/w) to about 12% (w/w). 64. The method of embodiment 54, wherein the nicotine 46. The method of any one of embodiments 1-40, wherein salt formulation comprises a nicotine Salt in a biologically the liquid formulation has a nicotine concentration of about acceptable liquid carrier wherein an acid used to form said 4% (w/w). nicotine salt is further characterized by a melting point at least 47. The method of any one of embodiments 1-40, wherein 25 40 degrees lower than the operating temperature of the elec the liquid formulation has a nicotine concentration of about tronic cigarette, a boiling point no more than 40 degrees lower 2% (w/w). than the operating temperature of the electronic cigarette, and 48. The method of any one of embodiments 1-47, wherein at least a 50-degree difference between the melting point and the formulation further comprises a flavorant. the boiling point; and the operating temperature is 200° C. 49. The method of any one of embodiments 1-48, wherein 30 65. The method of any one of embodiments 57-64, wherein the formulation is non-corrosive to an electronic cigarette. the Cmax is over 10 ng/mL on average. 50. The method of any one of embodiments 1-49, wherein 66. The methodofany one of embodiments 57-64, wherein the acid is stable at and below operating temperature or about the Cmax is over 11 ng/mL on average. 2009 C. 67. The method of any one of embodiments 57-64, wherein 51. The method of any one of embodiments 1-50, wherein 35 the Cmax is between 10 ng/mL and 16 ng/mL on average. the acid does not decompose at and below operating tempera 68. The method of any one of embodiments 57-64, wherein ture or about 200° C. the Cmax is between 11 ng/mL and 15 ng/mL on average. 52. The method of any one of embodiments 1-51, wherein 69. The method of any one of embodiments 57-64, wherein the acid does not oxidize at and below operating temperature the Cmax is between 11 ng/mL and 14 ng/mL on average. or about 200° C. 40 70. The method of any one of embodiments 57-69, wherein 53. The method of any one of embodiments 1-52, wherein the Tmax under 10 minutes on average. the formulation is non-corrosive to the electronic cigarette. 71. The method of any one of embodiments 57-69, wherein 54. The method of any one of embodiments 1-53, wherein the Tmax is under 9 minutes on average. the formulation is non-toxic to a user of the electronic ciga 72. The method of any one of embodiments 57-69, wherein rette. 45 the Tmax is under 8 minutes on average. 55. The method of any one of embodiments 1-54, wherein 73. The method of any one of embodiments 57-69, wherein the formulation further comprises one or more additional the Tmax is under 7 minutes on average. nicotine salts in a biologically acceptable liquid carrier Suit 74. The method of any one of embodiments 54-63, wherein able for generating the inhalable aerosol upon heating. the Tmax is from 3 minutes to 10 minutes on average. 56. The method of embodiment 55, wherein a second acid 50 75. The method of any one of embodiments 57-69, wherein used to form the additional nicotine salt is selected from the the Tmax is from 3 minutes to 7.5 minutes on average. group consisting of Salicylic acid, Sorbic acid, benzoic acid, 76. The method of any one of embodiments 57-75, wherein pyruvic acid, lauric acid, and levulinic acid. the aerosol comprises condensate of the nicotine salt. 57. A method of delivering nicotine to the blood of a user, 77. The method of any one of embodiments 57-75, wherein said method comprising providing an aerosol that is inhaled 55 the aerosol comprises condensate of freebase nicotine. by the user from an electronic cigarette that comprises a 78. The method of any one of embodiments 57-75, wherein nicotine salt formulation wherein providing the aerosol com the aerosol comprises condensate of freebase nicotine and prises the electronic cigarette heating the formulation thereby condensate of the carrier. generating the aerosol, wherein the aerosol is effective in 79. The method of any one of embodiments 57-75, wherein delivering a level of nicotine in the blood of the user that is at 60 the aerosol comprises condensate of freebase nicotine and least 5 ng/mL at about 1.5 minutes after a first puff often puffs condensate of the acid. of the aerosol, each puff taken at 30 second intervals. 80. The method of any one of embodiments 57-79, wherein 58. The method of embodiment 54, wherein the nicotine the aerosol comprises condensate in particle sizes from about salt formulation comprises a nicotine Salt in a biologically 0.1 microns to about 5 microns. acceptable liquid carrier wherein an acid used to form said 65 81. The method of any one of embodiments 57-79, wherein nicotine Salt is characterized by vapor pressure >20 mmHg at the aerosol comprises condensate in particle sizes from about 2009 C. 0.1 microns to about 1 or 2 microns. US 9,215,895 B2 33 34 82. The method of any one of embodiments 57-79, wherein 107. The method of any one of embodiments 57-105, the aerosol comprises condensate in particle sizes from about wherein the liquid formulation has a nicotine concentration of 0.1 microns to about 0.7 microns. about 1% (w/w) to about 20% (w/w). 83. The method of any one of embodiments 57-79, wherein 108. The method of any one of embodiments 57-105, the aerosol comprises condensate in particle sizes from about wherein the liquid formulation has a nicotine concentration of 0.3 microns to about 0.4 microns. about 1% (w/w) to about 18% (w/w). 84. The method of any one of embodiments 57-83, wherein 109. The method of any one of embodiments 57-105, the acid is a carboxylic acid. wherein the liquid formulation has a nicotine concentration of 85. The method of any one of embodiments 57-83, wherein about 1% (w/w) to about 15% (w/w). the acid used to form said nicotine salt is an organic acid. 10 86. The method of embodiment 85, wherein the organic 110. The method of any one of embodiments 57-105, acid is monocarboxylic acid, aromatic acid, or keto acid. wherein the liquid formulation has a nicotine concentration of 87. The method of embodiment 85, wherein the organic about 4% (w/w) to about 12% (w/w). acid is formic acid, acetic acid, propionic acid, butyric acid, 111. The method of any one of embodiments 57-105, Valeric acid, caproic acid, caprylic acid, capric acid, citric 15 wherein the liquid formulation has a nicotine concentration of acid, lauric acid, myristic acid, palmitic acid, Stearic acid, about 4% (w/w). oleic acid, linoleic acid, linolenic acid, phenylacetic acid, 112. The method of any one of embodiments 57-105, benzoic acid, pyruvic acid, levulinic acid, tartaric acid, lactic wherein the liquid formulation has a nicotine concentration of acid, malonic acid. Succinic acid, fumaric acid, finnaric acid, about 2% (w/w). gluconic acid, saccharic acid, Salicylic acid, Sorbic acid, mal 113. The method of any one of embodiments 57-112, onic acid, or malic acid. wherein the formulation further comprises a flavorant. 88. The method of any one of embodiments 57-83, wherein 114. The method of any one of embodiments 57-113, the acid used to form the nicotine salt is salicylic acid. wherein the formulation is non-corrosive to an electronic 89. The method of any one of embodiments 57-83, wherein cigarette. the acid used to form the nicotine salt is benzoic acid. 25 115. The method of any one of embodiments 57-114, 90. The method of any one of embodiments 57-83, wherein wherein the acid is stable at and below operating temperature the acid used to form the nicotine salt is pyruvic acid. or about 200° C. 91. The method of any one of embodiments 57-83, wherein 116. The method of any one of embodiments 57-115, the acid used to form the nicotine salt is sorbic acid. wherein the acid does not decompose at and below operating 92. The method of any one of embodiments 57-83, wherein 30 temperature or about 200° C. the acid used to form the nicotine salt is lauric acid. 117. The method of any one of embodiments 57-116. 93. The methodofany one of embodiments 57-83, wherein wherein the acid does not oxidize at and below operating the acid used to form the nicotine salt is levulinic acid. temperature or about 200° C. 94. The method of any one of embodiments 57-83, wherein 118. The method of any one of embodiments 57-117. said nicotine Salt comprises nicotine pyruvate. 35 wherein the formulation is non-corrosive to the electronic 95. The method of any one of embodiments 57-83, wherein cigarette. said nicotine Salt comprises nicotine salicylate. 119. The method of any one of embodiments 57-118, 96. The method of any one of embodiments 57-83, wherein wherein the formulation is non-toxic to a user of the elec said nicotine Salt comprises nicotine Sorbate. tronic cigarette. 97. The method of any one of embodiments 57-83, wherein 40 120. The method of any one of embodiments 57-119, said nicotine Salt comprises nicotine laurate. wherein the formulation further comprises one or more addi 98. The method of any one of embodiments 57-83, wherein tional nicotine salts in a biologically acceptable liquid carrier said nicotine Salt comprises nicotine levulinate. Suitable for generating the inhalable aerosol upon heating. 99. The method of any one of embodiments 57-83, wherein 121. The method of embodiment 120, wherein a second said nicotine Salt comprises nicotine benzoate. 45 acid used to form the additional nicotine salt is selected from 100. The method of any one of embodiments 57-99, the group consisting of salicylic acid, Sorbic acid, benzoic wherein the liquid carrier comprises glycerol, propylene gly acid, pyruvic acid, lauric acid, and levulinic acid. col, trimethylene glycol, water, ethanol or combinations 122. A nicotine salt liquid formulation in an electronic thereof. cigarette for generating an inhalable aerosol upon heating in 101. The method of any one of embodiments 57-99, 50 the electronic cigarette, the formulation in the cigarette com wherein the liquid carrier comprises propylene glycol and prising a nicotine salt in a biologically acceptable liquid car Vegetable glycerin. rier wherein an acid used to form said nicotine Salt is charac 102. The method of any one of embodiments 57-99, terized by vapor pressure >20 mmHg at 200° C. wherein the liquid carrier comprises 20% to 50% of propy 123. A nicotine salt liquid formulation in an electronic lene glycol and 80% to 50% of vegetable glycerin. 55 cigarette for generating an inhalable aerosol upon heating in 103. The method of any one of embodiments 57-99, the electronic cigarette, the formulation in the cigarette com wherein the liquid carrier comprises 30% propylene glycol prising a nicotine salt in a biologically acceptable liquid car and 70% vegetable glycerin. rier wherein an acid used to form said nicotine Salt is charac 104. The method of any one of embodiments 57-103, terized by vapor pressure of about 20 to 200 mmHg at 200° C. wherein the nicotine salt is in an amount that forms about 60 124. A nicotine salt liquid formulation in an electronic 0.5% to about 20% nicotine in the inhalable aerosol. cigarette for generating an inhalable aerosol upon heating in 105. The method of any one of embodiments 57-103, the electronic cigarette, the formulation in the cigarette com wherein the nicotine salt is in an amount that forms about 1% prising a nicotine salt in a biologically acceptable liquid car to about 20% nicotine in the inhalable aerosol. rier wherein an acid used to form said nicotine salt is further 106. The method of any one of embodiments 57-105, 65 characterized by a melting point <160° C., a boiling point wherein the liquid formulation has a nicotine concentration of >160° C., and at least a 50-degree difference between the about 1% (w/w) to about 25% (w/w). melting point and the boiling point. US 9,215,895 B2 35 36 125. A nicotine salt liquid formulation in an electronic 141. The nicotine salt liquid formulation in the electronic cigarette for generating an inhalable aerosol upon heating in cigarette of any one of embodiments 122-131, wherein the the electronic cigarette, the formulation in the cigarette com acid used to form the nicotine salt is levulinic acid. prising a nicotine salt in a biologically acceptable liquid car 142. The nicotine salt liquid formulation in the electronic rier wherein an acid used to form said nicotine salt is further cigarette of any one of embodiments 122-131, wherein said characterized by a melting point at least 40 degrees lower than nicotine Salt comprises nicotine pyruvate. an operating temperature of the electronic cigarette, a boiling 143. The nicotine salt liquid formulation in the electronic point no more than 40 degrees lower than the operating tem cigarette of any one of embodiments 122-131, wherein said perature of the electronic cigarette, and at least a 50-degree nicotine Salt comprises nicotine salicylate. difference between the melting point and the boiling point. 10 144. The nicotine salt liquid formulation in the electronic 126. The nicotine salt liquid formulation in the electronic cigarette of any one of embodiments 122-131, wherein said cigarette of any one of embodiments 122-124, wherein the nicotine Salt comprises nicotine Sorbate. electronic cigarette heats the nicotine salt formulation to an 145. The nicotine salt liquid formulation in the electronic operating temperature from 150° C. to 250° C. 15 cigarette of any one of embodiments 122-131, wherein said 127. The nicotine salt liquid formulation in the electronic nicotine Salt comprises nicotine laurate. cigarette of any one of embodiments 122-124, wherein the 146. The nicotine salt liquid formulation in the electronic electronic cigarette heats the nicotine salt formulation to an cigarette of any one of embodiments 122-131, wherein said operating temperature from 180° C. to 220° C. nicotine Salt comprises nicotine levulinate. 128. The nicotine salt liquid formulation in the electronic 147. The nicotine salt liquid formulation in the electronic cigarette of any one of embodiments 122-124, wherein the cigarette of any one of embodiments 122-131, wherein said electronic cigarette heats the nicotine salt formulation to an nicotine Salt comprises nicotine benzoate. operating temperature of about 200° C. 148. The nicotine salt liquid formulation in the electronic 129. The nicotine salt liquid formulation in the electronic cigarette of any one of embodiments 122-147, wherein the cigarette of embodiment 125, wherein the operating tempera 25 liquid carrier comprises glycerol, propylene glycol, trimeth ture is from 150° C. to 250° C. ylene glycol, water, ethanol or combinations thereof. 130. The nicotine salt liquid formulation in the electronic 149. The nicotine salt liquid formulation in the electronic cigarette of embodiment 125, wherein the operating tempera cigarette of any one of embodiments 122-147, wherein the ture is from 180° C. to 220° C. liquid carrier comprises propylene glycol and vegetable glyc 131. The nicotine salt liquid formulation in the electronic 30 erin. cigarette of embodiment 125, wherein the operating tempera 150. The nicotine salt liquid formulation in the electronic ture is about 200° C. cigarette of any one of embodiments 122-147, wherein the 132. The nicotine salt liquid formulation in the electronic liquid carrier comprises 20% to 50% of propylene glycol and cigarette of any one of embodiments 122-131, wherein the 35 80% to 50% of vegetable glycerin. acid is a carboxylic acid. 151. The nicotine salt liquid formulation in the electronic 133. The nicotine salt liquid formulation in the electronic cigarette of any one of embodiments 122-147, wherein the cigarette of any one of embodiments 122-131, wherein the liquid carrier comprises 30% propylene glycol and 70% veg acid used to form said nicotine Salt is an organic acid. etable glycerin. 134. The nicotine salt liquid formulation in the electronic 40 152. The nicotine salt liquid formulation in the electronic cigarette of embodiment 133, wherein the organic acid is cigarette of any one of embodiments 122-151, wherein the monocarboxylic acid, aromatic acid, or keto acid. nicotine salt is in an amount that forms about 0.5% to about 135. The nicotine salt liquid formulation in the electronic 20% nicotine in the inhalable aerosol. cigarette of embodiment 133, wherein the organic acid is 153. The nicotine salt liquid formulation in the electronic formic acid, acetic acid, propionic acid, butyric acid, Valeric 45 cigarette of any one of embodiments 122-151, wherein the acid, caproic acid, caprylic acid, capric acid, citric acid, lauric nicotine salt is in an amount that forms about 1% to about acid, myristic acid, palmitic acid, Stearic acid, oleic acid, 20% nicotine in the inhalable aerosol. linoleic acid, linolenic acid, phenylacetic acid, benzoic acid, 154. The nicotine salt liquid formulation in the electronic pyruvic acid, levulinic acid, tartaric acid, lactic acid, malonic cigarette of any one of embodiments 122-153, wherein the acid, Succinic acid, fumaric acid, finnaric acid, gluconic acid, 50 liquid formulation has a nicotine concentration of about 1% saccharic acid, Salicylic acid, Sorbic acid, malonic acid, or (w/w) to about 25% (w/w). malic acid. 155. The nicotine salt liquid formulation in the electronic 136. The nicotine salt liquid formulation in the electronic cigarette of any one of embodiments 122-153, wherein the cigarette of any one of embodiments 122-131, wherein the liquid formulation has a nicotine concentration of about 1% acid used to form the nicotine salt is salicylic acid. 55 (w/w) to about 20% (w/w). 137. The nicotine salt liquid formulation in the electronic 156. The nicotine salt liquid formulation in the electronic cigarette of any one of embodiments 122-131, wherein the cigarette of any one of embodiments 122-153, wherein the acid used to form the nicotine salt is benzoic acid. liquid formulation has a nicotine concentration of about 1% 138. The nicotine salt liquid formulation in the electronic (w/w) to about 18% (w/w). cigarette of any one of embodiments 122-131, wherein the 60 157. The nicotine salt liquid formulation in the electronic acid used to form the nicotine salt is pyruvic acid. cigarette of any one of embodiments 122-153, wherein the 139. The nicotine salt liquid formulation in the electronic liquid formulation has a nicotine concentration of about 1% cigarette of any one of embodiments 122-131, wherein the (w/w) to about 15% (w/w). acid used to form the nicotine salt is Sorbic acid. 158. The nicotine salt liquid formulation in the electronic 140. The nicotine salt liquid formulation in the electronic 65 cigarette of any one of embodiments 122-153, wherein the cigarette of any one of embodiments 122-131, wherein the liquid formulation has a nicotine concentration of about 4% acid used to form the nicotine salt is lauric acid. (w/w) to about 12% (w/w). US 9,215,895 B2 37 38 159. The nicotine salt liquid formulation in the electronic point at least 40 degrees lower than an operating temperature cigarette of any one of embodiments 122-153, wherein the of the electronic cigarette, a boiling point no more than 40 liquid formulation has a nicotine concentration of about 4% degrees lower than the operating temperature of the electronic (w/w). cigarette, and at least a 50-degree difference between the 160. The nicotine salt liquid formulation in the electronic melting point and the boiling point. cigarette of any one of embodiments 122-153, wherein the 174. The nicotine salt liquid formulation of any one of liquid formulation has a nicotine concentration of about 2% embodiments 170-172, wherein the electronic cigarette heats (w/w). the nicotine Saltformulation to an operating temperature from 161. The nicotine salt liquid formulation in the electronic 150° C. to 2500 C. cigarette of any one of embodiments 122-160, wherein the 10 formulation further comprises a flavorant. 175. The nicotine salt liquid formulation of any one of 162. The nicotine salt liquid formulation in the electronic embodiments 170-172, wherein the electronic cigarette heats cigarette of any one of embodiments 122-161, wherein the the nicotine Saltformulation to an operating temperature from formulation is non-corrosive to an electronic cigarette. 180° C. to 220° C. 163. The nicotine salt liquid formulation in the electronic 15 176. The nicotine salt liquid formulation of any one of cigarette of any one of embodiments 122-162, wherein the embodiments 170-172, wherein the electronic cigarette heats acid is stable at and below operating temperature or about the nicotine salt formulation to an operating temperature of 2009 C. about 200° C. 164. The nicotine salt liquid formulation in the electronic 177. The nicotine salt liquid formulation of embodiment cigarette of any one of embodiments 122-163, wherein the 173, wherein the operating temperature is from 150° C. to acid does not decompose at and below operating temperature 2500 C. or about 200° C. 178. The nicotine salt liquid formulation of embodiment 165. The nicotine salt liquid formulation in the electronic 173, wherein the operating temperature is from 180° C. to cigarette of any one of embodiments 122-164, wherein the 2200 C. acid does not oxidize at and below operating temperature or 25 179. The nicotine salt liquid formulation of embodiment about 200° C. 173, wherein the operating temperature is about 200° C. 166. The nicotine salt liquid formulation in the electronic 180. The nicotine salt liquid formulation of any one of cigarette of any one of embodiments 122-165, wherein the embodiments 170-179, wherein the acid is a carboxylic acid. formulation is non-corrosive to the electronic cigarette. 181. The nicotine salt liquid formulation of any one of 167. The nicotine salt liquid formulation in the electronic 30 embodiments 170-179, wherein the acid used to form said cigarette of any one of embodiments 122-166, wherein the nicotine Salt is an organic acid. formulation is non-toxic to a user of the electronic cigarette. 182. The nicotine salt liquid formulation of embodiment 168. The nicotine salt liquid formulation in the electronic 181, wherein the organic acid is monocarboxylic acid, aro cigarette of any one of embodiments 122-167 further com matic acid, or keto acid. prising one or more additional nicotine salts in a biologically 35 183. The nicotine salt liquid formulation of embodiment acceptable liquid carrier Suitable for generating the inhalable 181, wherein the organic acid is formic acid, acetic acid, aerosol upon heating. propionic acid, butyric acid, Valeric acid, caproic acid, 169. The nicotine salt liquid formulation in the electronic caprylic acid, capric acid, citric acid, lauric acid, myristic cigarette of embodiment 168, wherein a second acid used to acid, palmitic acid, Stearic acid, oleic acid, linoleic acid, form the additional nicotine salt is selected from the group 40 linolenic acid, phenylacetic acid, benzoic acid, pyruvic acid, consisting of salicylic acid, Sorbic acid, benzoic acid, pyruvic levulinic acid, tartaric acid, lactic acid, malonic acid, Succinic acid, lauric acid, and levulinic acid. acid, fumaric acid, finnaric acid, gluconic acid, saccharic 170. A nicotine salt liquid formulation for generating an acid, salicylic acid, Sorbic acid, malonic acid, or malic acid. inhalable aerosol upon heating in the electronic cigarette, the 184. The liquid formulation of any one of embodiments nicotine salt liquid formulation comprising a nicotine salt in a 45 170-179, wherein the acid used to form the nicotine salt is biologically acceptable liquid carrier wherein an acid used to salicylic acid. form said nicotine salt is characterized by vapor pressure >20 185. The nicotine salt liquid formulation of any one of mmHg at 200° C. embodiments 170-179, wherein the acid used to form the 171. A nicotine salt liquid formulation for generating an nicotine Salt is benzoic acid. inhalable aerosol upon heating in the electronic cigarette, the 50 186. The nicotine salt liquid formulation of any one of nicotine salt liquid formulation comprising a nicotine salt in a embodiments 170-179, wherein the acid used to form the biologically acceptable liquid carrier wherein an acid used to nicotine Salt is pyruvic acid. form said nicotine salt is characterized by vapor pressure of 187. The nicotine salt liquid formulation of any one of about 20 to 200 mmHg at 200° C. embodiments 170-179, wherein the acid used to form the 172. A nicotine salt liquid formulation for generating an 55 nicotine Salt is Sorbic acid. inhalable aerosol upon heating in the electronic cigarette, the 188. The nicotine salt liquid formulation of any one of nicotine salt liquid formulation comprising a nicotine salt in a embodiments 170-179, wherein the acid used to form the biologically acceptable liquid carrier wherein an acid used to nicotine Salt is lauric acid. form said nicotine salt is further characterized by a melting 189. The nicotine salt liquid formulation of any one of point <160° C., a boiling point >160° C., and at least a 60 embodiments 170-179, wherein the acid used to form the 50-degree difference between the melting point and the boil nicotine Salt is levulinic acid. ing point. 190. The nicotine salt liquid formulation of any one of 173. A nicotine salt liquid formulation for generating an embodiments 170-179, wherein said nicotine salt comprises inhalable aerosol upon heating in the electronic cigarette, the nicotine pyruvate. nicotine salt liquid formulation comprising a nicotine salt in a 65 191. The nicotine salt liquid formulation of any one of biologically acceptable liquid carrier wherein an acid used to embodiments 170-179, wherein said nicotine salt comprises form said nicotine salt is further characterized by a melting nicotine Salicylate. US 9,215,895 B2 39 40 192. The nicotine salt liquid formulation of any one of 211. The nicotine salt liquid formulation of any one of embodiments 170-179, wherein said nicotine salt comprises embodiments 170-210, wherein the acid is stable at and nicotine Sorbate. below operating temperature or about 200° C. 193. The nicotine salt liquid formulation of any one of 212. The nicotine salt liquid formulation of any one of embodiments 170-179, wherein said nicotine salt comprises embodiments 170-211, wherein the acid does not decompose nicotine laurate. at and below operating temperature or about 200° C. 194. The nicotine salt liquid formulation of any one of 213. The nicotine salt liquid formulation of any one of embodiments 170-179, wherein said nicotine salt comprises embodiments 170-212, wherein the acid does not oxidize at nicotine levulinate. and below operating temperature or about 200° C. 195. The nicotine salt liquid formulation of any one of 10 214. The nicotine salt liquid formulation of any one of embodiments 170-179, wherein said nicotine salt comprises embodiments 170-213, wherein the formulation is non-cor nicotine benzoate. rosive to the electronic cigarette. 196. The nicotine salt liquid formulation of any one of 215. The nicotine salt liquid formulation of any one of embodiments 170-195, wherein the liquid carrier comprises 15 embodiments 170-214, wherein the formulation is non-toxic glycerol, propylene glycol, trimethylene glycol, water, etha to a user of the electronic cigarette. nol or combinations thereof. 216. The nicotine salt liquid formulation of any one of 197. The nicotine salt liquid formulation of any one of embodiments 170-215, further comprising one or more addi embodiments 170-195, wherein the liquid carrier comprises tional nicotine salts in a biologically acceptable liquid carrier propylene glycol and vegetable glycerin. Suitable for generating the inhalable aerosol upon heating. 198. The nicotine salt liquid formulation of any one of 217. The nicotine salt liquid formulation of embodiment embodiments 170-195, wherein the liquid carrier comprises 216, wherein a second acid used to form the additional nico 20% to 50% of propylene glycoland 80% to 50% of vegetable tine salt is selected from the group consisting of salicylic acid, glycerin. Sorbic acid, benzoic acid, pyruvic acid, lauric acid, and 199. The nicotine salt liquid formulation of any one of 25 levulinic acid. embodiments 170-195, wherein the liquid carrier comprises 218. A nicotine salt liquid formulation for use in an elec 30% propylene glycol and 70% vegetable glycerin. tronic cigarette the nicotine salt liquid formulation compris 200. The nicotine salt liquid formulation of any one of ing a nicotine salt in a biologically acceptable liquid carrier embodiments 170-199, wherein the nicotine salt is in an wherein an acid used to form said nicotine salt is character amount that forms about 0.5% to about 20% nicotine in the 30 inhalable aerosol. ized by vapor pressure >20 mmHg at 200° C. 201. The nicotine salt liquid formulation of any one of 219. A nicotine salt liquid formulation for use in an elec embodiments 170-199, wherein the nicotine salt is in an tronic cigarette the nicotine salt liquid formulation compris amount that forms about 1% to about 20% nicotine in the ing a nicotine salt in a biologically acceptable liquid carrier wherein an acid used to form said nicotine salt is character inhalable aerosol. 35 202. The nicotine salt liquid formulation of any one of ized by vapor pressure of about 20 to 200 mmHg at 200°C. embodiments 170-201, wherein the liquid formulation has a 220. A nicotine salt liquid formulation for use in an elec nicotine concentration of about 1% (w/w) to about 25% tronic cigarette the nicotine salt liquid formulation compris (w/w). ing a nicotine salt in a biologically acceptable liquid carrier 203. The nicotine salt liquid formulation of any one of 40 wherein an acid used to form said nicotine salt is further embodiments 170-201, wherein the liquid formulation has a characterized by a melting point <160° C., a boiling point nicotine concentration of about 1% (w/w) to about 20% >160° C., and at least a 50-degree difference between the (w/w). melting point and the boiling point. 204. The nicotine salt liquid formulation of any one of 221. A nicotine salt liquid formulation for use in an elec embodiments 170-201, wherein the liquid formulation has a 45 tronic cigarette the nicotine salt liquid formulation compris nicotine concentration of about 1% (w/w) to about 18% ing a nicotine salt in a biologically acceptable liquid carrier (w/w). wherein an acid used to form said nicotine salt is further 205. The nicotine salt liquid formulation of any one of characterized by a melting point at least 40 degrees lower than embodiments 170-201, wherein the liquid formulation has a an operating temperature of the electronic cigarette, a boiling nicotine concentration of about 1% (w/w) to about 15% 50 point no more than 40 degrees lower than the operating tem (w/w). perature of the electronic cigarette, and at least a 50-degree 206. The nicotine salt liquid formulation of any one of difference between the melting point and the boiling point. embodiments 170-201, wherein the liquid formulation has a 222. The nicotine salt liquid formulation of any one of nicotine concentration of about 4% (w/w) to about 12% embodiments 218-220, wherein the electronic cigarette heats (w/w). 55 the nicotine Saltformulation to an operating temperature from 207. The nicotine salt liquid formulation of any one of 150° C. to 2500 C. embodiments 170-201, wherein the liquid formulation has a 223. The nicotine salt liquid formulation of any one of nicotine concentration of about 4% (w/w). embodiments 218-220, wherein the electronic cigarette heats 208. The nicotine salt liquid formulation of any one of the nicotine Saltformulation to an operating temperature from embodiments 170-201, wherein the liquid formulation has a 60 180° C. to 220° C. nicotine concentration of about 2% (w/w). 224. The nicotine salt liquid formulation of any one of 209. The nicotine salt liquid formulation of any one of embodiments 218-220, wherein the electronic cigarette heats embodiments 170-208, wherein the formulation further com the nicotine salt formulation to an operating temperature of prises a flavorant. about 200° C. 210. The nicotine salt liquid formulation of any one of 65 225. The nicotine salt liquid formulation of embodiment embodiments 170-209, wherein the formulation is non-cor 221, wherein the operating temperature is from 150° C. to rosive to an electronic cigarette. 2500 C. US 9,215,895 B2 41 42 226. The nicotine salt liquid formulation of embodiment 246. The nicotine salt liquid formulation of any one of 221, wherein the operating temperature is from 180° C. to embodiments 218-243, wherein the liquid carrier comprises 2200 C. 20% to 50% of propylene glycoland 80% to 50% of vegetable 227. The nicotine salt liquid formulation of embodiment glycerin. 221, wherein the operating temperature is about 200° C. 5 247. The nicotine salt liquid formulation of any one of 228. The nicotine salt liquid formulation of any one of embodiments 218-243, wherein the liquid carrier comprises embodiments 218-227, wherein the acid is a carboxylic acid. 30% propylene glycol and 70% vegetable glycerin. 229. The nicotine salt liquid formulation of any one of 248. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein the acid used to form said embodiments 218-247, wherein the nicotine salt is in an nicotine salt is an organic acid. 10 amount that forms about 0.5% to about 20% nicotine in the 230. The nicotine salt liquid formulation of embodiment inhalable aerosol. 229, wherein the organic acid is monocarboxylic acid, aro 249. The nicotine salt liquid formulation of any one of matic acid, or keto acid. embodiments 218-247, wherein the nicotine salt is in an 231. The nicotine salt liquid formulation of embodiment 15 amount that forms about 1% to about 20% nicotine in the 229, wherein the organic acid is formic acid, acetic acid, inhalable aerosol. propionic acid, butyric acid, Valeric acid, caproic acid, 250. The nicotine salt liquid formulation of any one of caprylic acid, capric acid, citric acid, lauric acid, myristic embodiments 218-247, wherein the liquid formulation has a acid, palmitic acid, Stearic acid, oleic acid, linoleic acid, nicotine concentration of about 1% (w/w) to about 25% linolenic acid, phenylacetic acid, benzoic acid, pyruvic acid, (w/w). levulinic acid, tartaric acid, lactic acid, malonic acid, Succinic 251. The nicotine salt liquid formulation of any one of acid, fumaric acid, finnaric acid, gluconic acid, saccharic embodiments 218-247, wherein the liquid formulation has a acid, salicylic acid, Sorbic acid, malonic acid, or malic acid. nicotine concentration of about 1% (w/w) to about 20% 232. The liquid formulation of any one of embodiments (w/w). 218-227, wherein the acid used to form the nicotine salt is 25 252. The nicotine salt liquid formulation of any one of salicylic acid. embodiments 218-247, wherein the liquid formulation has a 233. The nicotine salt liquid formulation of any one of nicotine concentration of about 1% (w/w) to about 18% embodiments 218-227, wherein the acid used to form the (w/w). nicotine salt is benzoic acid. 253. The nicotine salt liquid formulation of any one of 234. The nicotine salt liquid formulation of any one of 30 embodiments 218-247, wherein the liquid formulation has a nicotine concentration of about 1% (w/w) to about 15% embodiments 218-227, wherein the acid used to form the (w/w). nicotine salt is pyruvic acid. 254. The nicotine salt liquid formulation of any one of 235. The nicotine salt liquid formulation of any one of embodiments 218-247, wherein the liquid formulation has a embodiments 218-227, wherein the acid used to form the 35 nicotine concentration of about 4% (w/w) to about 12% nicotine salt is Sorbic acid. (w/w). 236. The nicotine salt liquid formulation of any one of 255. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein the acid used to form the embodiments 218-247, wherein the liquid formulation has a nicotine salt is lauric acid. nicotine concentration of about 4% (w/w). 237. The nicotine salt liquid formulation of any one of 40 256. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein the acid used to form the embodiments 218-247, wherein the liquid formulation has a nicotine salt is levulinic acid. nicotine concentration of about 2% (w/w). 238. The nicotine salt liquid formulation of any one of 257. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein said nicotine salt comprises embodiments 218-256, wherein the formulation further com nicotine pyruvate. 45 prises a flavorant. 239. The nicotine salt liquid formulation of any one of 258. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein said nicotine salt comprises embodiments 218-257, wherein the formulation is non-cor nicotine salicylate. rosive to an electronic cigarette. 240. The nicotine salt liquid formulation of any one of 259. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein said nicotine salt comprises 50 embodiments 218-258, wherein the acid is stable at and nicotine Sorbate. below operating temperature or about 200° C. 241. The nicotine salt liquid formulation of any one of 260. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein said nicotine salt comprises embodiments 218-259, wherein the acid does not decompose nicotine laurate. at and below operating temperature or about 200° C. 242. The nicotine salt liquid formulation of any one of 55 261. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein said nicotine salt comprises embodiments 218-260, wherein the acid does not oxidize at nicotine levulinate. and below operating temperature or about 200° C. 243. The nicotine salt liquid formulation of any one of 262. The nicotine salt liquid formulation of any one of embodiments 218-227, wherein said nicotine salt comprises embodiments 218-261, wherein the formulation is non-cor nicotine benzoate. 60 rosive to the electronic cigarette. 244. The nicotine salt liquid formulation of any one of 263. The nicotine salt liquid formulation of any one of embodiments 218-243, wherein the liquid carrier comprises embodiments 218-262, wherein the formulation is non-toxic glycerol, propylene glycol, trimethylene glycol, water, etha to a user of the electronic cigarette. nol or combinations thereof. 264. The nicotine salt liquid formulation of any one of 245. The nicotine salt liquid formulation of any one of 65 embodiments 218-263, further comprising one or more addi embodiments 218-243, wherein the liquid carrier comprises tional nicotine salts in a biologically acceptable liquid carrier propylene glycol and vegetable glycerin. Suitable for generating the inhalable aerosol upon heating. US 9,215,895 B2 43 44 265. The nicotine salt liquid formulation of embodiment 278. The use of any one of embodiments 266-276, wherein 264, wherein a second acid used to form the additional nico the aerosol comprises condensate of freebase nicotine. tine salt is selected from the group consisting of salicylic acid, 279. The use of any one of embodiments 266-276, wherein Sorbic acid, benzoic acid, pyruvic acid, lauric acid, and the aerosol comprises condensate of freebase nicotine and levulinic acid. 5 condensate of the carrier. 266. Use of a nicotine salt formulation for delivery of 280. The use of any one of embodiments 266-276, wherein nicotine to a user from an electronic cigarette wherein the the aerosol comprises condensate of freebase nicotine and nicotine salt formulation comprises a nicotine salt in a bio condensate of the acid. logically acceptable liquid carrier wherein an acid used to 281. The use of any one of embodiments 266-280, wherein form said nicotine salt is characterized by vapor pressure >20 10 mmHg at 200°C., and the nicotine salt formulation is heated the aerosol comprises condensate in particle sizes from about by the electronic cigarette to generate anaerosol inhalable by 0.1 microns to about 5 microns. the user. 282. The use of any one of embodiments 266-280, wherein the aerosol comprises condensate in particle sizes from about 267. Use of a nicotine salt formulation for delivery of 0.1 microns to about 1 or 2 microns. nicotine to a user from an electronic cigarette wherein the 15 nicotine salt formulation comprises a nicotine salt in a bio 283. The use of any one of embodiments 266-280, wherein logically acceptable liquid carrier wherein an acid used to the aerosol comprises condensate in particle sizes from about form said nicotine salt is characterized by vapor pressure of 0.1 microns to about 0.7 microns. about 20 to 200 mmHg at 200° C., and the nicotine salt 284. The use of any one of embodiments 266-280, wherein formulation is heated by the electronic cigarette to generate the aerosol comprises condensate in particle sizes from about an aerosol inhalable by the user. 0.3 microns to about 0.4 microns. 268. Use of a nicotine salt formulation for delivery of 285. The use of any one of embodiments 266-284, wherein nicotine to a user from an electronic cigarette wherein the the acid is a carboxylic acid. nicotine salt formulation comprises a nicotine salt in a bio 286. The use of any one of embodiments 266-284, wherein logically acceptable liquid carrier wherein an acid used to 25 the acid used to form said nicotine salt is an organic acid. form said nicotine salt is further characterized by a melting 287. The use of embodiment 286, wherein the organic acid point <160° C., a boiling point >160° C., and at least a is monocarboxylic acid, aromatic acid, or keto acid. 50-degree difference between the melting point and the boil 288. The use of embodiment 286, wherein the organic acid ing point, and the nicotine salt formulation is heated by the is formic acid, acetic acid, propionic acid, butyric acid, electronic cigarette to generate an aerosol inhalable by the 30 Valeric acid, caproic acid, caprylic acid, capric acid, citric USC. 269. Use of a nicotine salt formulation for delivery of acid, lauric acid, myristic acid, palmitic acid, Stearic acid, nicotine to the blood of a user from an electronic cigarette, oleic acid, linoleic acid, linolenic acid, phenylacetic acid, wherein the nicotine salt formulation in the electronic ciga benzoic acid, pyruvic acid, levulinic acid, tartaric acid, lactic rette is heated to form an aerosol which delivers a level of 35 acid, malonic acid. Succinic acid, fumaric acid, finnaric acid, nicotine in the blood of the user that is at least 5 ng/mL at gluconic acid, saccharic acid, Salicylic acid, Sorbic acid, mal about 1.5 minutes after a first puff often puffs of the aerosol, onic acid, or malic acid. each pufftaken at 30 second intervals. 289. The use of any one of embodiments 266-284, wherein 270. Use of a nicotine salt formulation for delivery of the acid used to form the nicotine salt is salicylic acid. nicotine to a user from an electronic cigarette wherein the 40 290. The use of any one of embodiments 266-284, wherein nicotine salt formulation comprises a nicotine salt in a bio the acid used to form the nicotine salt is benzoic acid. logically acceptable liquid carrier wherein an acid used to 291. The use of any one of embodiments 266-284, wherein form said nicotine salt is further characterized by a melting the acid used to form the nicotine salt is pyruvic acid. point at least 40 degrees lower than an operating temperature 292. The use of any one of embodiments 266-284, wherein of the electronic cigarette, a boiling point no more than 40 45 the acid used to form the nicotine salt is sorbic acid. degrees lower than the operating temperature of the electronic 293. The use of any one of embodiments 266-284, wherein cigarette, and at least a 50-degree difference between the the acid used to form the nicotine salt is lauric acid. melting point and the boiling point, and the nicotine salt 294. The use of any one of embodiments 266-284, wherein formulation is heated by the electronic cigarette to generate the acid used to form the nicotine salt is levulinic acid. an aerosol inhalable by the user. 50 295. The use of any one of embodiments 266-284, wherein 271. The use of any one of embodiments 266-269, wherein said nicotine salt comprises nicotine pyruvate. the electronic cigarette heats the nicotine Salt formulation to 296. The use of any one of embodiments 266-284, wherein an operating temperature is from 150° C. to 250° C. said nicotine salt comprises nicotine Salicylate. 272. The use of any one of embodiments 266-269, wherein 297. The use of any one of embodiments 266-284, wherein the electronic cigarette heats the nicotine Salt formulation to 55 said nicotine salt comprises nicotine Sorbate. an operating temperature is from 180° C. to 220° C. 298. The use of any one of embodiments 266-284, wherein 273. The use of any one of embodiments 266-269, wherein said nicotine salt comprises nicotine laurate. the electronic cigarette heats the nicotine Salt formulation to 299. The use of any one of embodiments 266-284, wherein an operating temperature is about 200° C. said nicotine salt comprises nicotine levulinate. 274. The use of embodiment 270, wherein the operating 60 300. The use of any one of embodiments 266-284, wherein temperature is from 150° C. to 250° C. said nicotine salt comprises nicotine benzoate. 275. The use of embodiment 270, wherein the operating 301. The use of any one of embodiments 266-300, wherein temperature is from 180° C. to 220° C. the liquid carrier comprises glycerol, propylene glycol, trim 276. The use of embodiment 270, wherein the operating ethylene glycol, water, ethanol or combinations thereof. temperature is about 200°C. 65 302. The use of any one of embodiments 266-300, wherein 277. The use of any one of embodiments 266-276, wherein the liquid carrier comprises propylene glycol and vegetable the aerosol comprises condensate of the nicotine salt. glycerin. US 9,215,895 B2 45 46 303. The use of any one of embodiments 266-300, wherein a fluid storage compartment that stores the nicotine salt the liquid carrier comprises 20% to 50% of propylene glycol liquid formulation. and 80% to 50% of vegetable glycerin. 324. A cartomizer for an electronic cigarette comprising: 304. The use of any one of embodiments 266-300, wherein a nicotine salt liquid formulation comprising a nicotine salt the liquid carrier comprises 30% propylene glycol and 70% in a biologically acceptable liquid carrier wherein an Vegetable glycerin. acid used to form said nicotine salt is characterized by 305. The use of any one of embodiments 266-304, wherein vapor pressure of about 20 to 200 mmHg at 200° C.; the nicotine salt is in an amount that forms about 0.5% to an atomizer comprising a heating element in fluid commu about 20% nicotine in the inhalable aerosol. nication with the nicotine salt liquid formulation; and 10 a fluid storage compartment that stores the nicotine salt 306. The use of any one of embodiments 266-304, wherein liquid formulation. the nicotine salt is in an amount that forms about 1% to about 325. A cartomizer for an electronic cigarette comprising: 20% nicotine in the inhalable aerosol. a nicotine salt liquid formulation comprising a nicotine salt 307. The use of any one of embodiments 266-306, wherein in a biologically acceptable liquid carrier wherein an the liquid formulation has a nicotine concentration of about 15 acid used to form said nicotine salt is further character 1% (w/w) to about 25% (w/w). ized by a melting point <160° C., a boiling point >160° 308. The use of any one of embodiments 266-306, wherein C., and at least a 50-degree difference between the melt the liquid formulation has a nicotine concentration of about ing point and the boiling point; 1% (w/w) to about 20% (w/w). an atomizer comprising a heating element in fluid commu 309. The use of any one of embodiments 266-306, wherein nication with the nicotine salt liquid formulation; and the liquid formulation has a nicotine concentration of about a fluid storage compartment that stores the nicotine salt 1% (w/w) to about 18% (w/w). liquid formulation. 310. The use of any one of embodiments 266-306, wherein 326. A cartomizer for an electronic cigarette comprising: the liquid formulation has a nicotine concentration of about a nicotine salt liquid formulation comprising a nicotine salt 1% (w/w) to about 15% (w/w). 25 in a biologically acceptable liquid carrier wherein an 311. The use of any one of embodiments 266-306, wherein acid used to form said nicotine salt is further character the liquid formulation has a nicotine concentration of about ized by a melting point at least 40 degrees lower than an 4% (w/w) to about 12% (w/w). operating temperature of the electronic cigarette, a boil 312. The use of any one of embodiments 266-306, wherein ing point no more than 40 degrees lower than the oper the liquid formulation has a nicotine concentration of about 30 ating temperature of the electronic cigarette, and at least 4% (w/w). a 50-degree difference between the melting point and the 313. The use of any one of embodiments 266-306, wherein boiling point; the liquid formulation has a nicotine concentration of about an atomizer comprising a heating element in fluid commu 2% (w/w). nication with the nicotine salt liquid formulation; and 314. The use of any one of embodiments 266-313, wherein 35 a fluid storage compartment that stores the nicotine salt the formulation further comprises a flavorant. liquid formulation. 315. The use of any one of embodiments 266-314, wherein 327. The cartomizer of any one of embodiments 323-325, the formulation is non-corrosive to an electronic cigarette. wherein the electronic cigarette heats the nicotine Saltformu 316. The use of any one of embodiments 266-315, wherein lation to an operating temperature from 150° C. to 250° C. the acid is stable at and below operating temperature or about 40 328. The cartomizer of any one of embodiments 323-325, 2009 C. wherein the electronic cigarette heats the nicotine Saltformu 317. The use of any one of embodiments 266-316, wherein lation to an operating temperature from 180° C. to 220° C. the acid does not decompose at and below operating tempera 329. The cartomizer of any one of embodiments 323-325, ture or about 200° C. wherein the electronic cigarette heats the nicotine Saltformu 318. The use of any one of embodiments 266-317, wherein 45 lation to an operating temperature of about 200°C. the acid does not oxidize at and below operating temperature 330. The cartomizer of embodiment 326, wherein the oper or about 200° C. ating temperature is from 150° C. to 250° C. 319. The use of any one of embodiments 266-318, wherein 331. The cartomizer of embodiment 326, wherein the oper the formulation is non-corrosive to the electronic cigarette. ating temperature is from 180°C. to 220° C. 320. The use of any one of embodiments 266-319, wherein 50 332. The cartomizer of embodiment 326, wherein the oper the formulation is non-toxic to a user of the electronic ciga ating temperature is about 200° C. rette. 333. The cartomizer of any one of embodiments 323-332, 321. The use of any one of embodiments 266-320, wherein wherein the cartomizer further comprises a mouthpiece. the formulation further comprises one or more additional 334. The cartomizer of any one of embodiments 323-333, nicotine salts in a biologically acceptable liquid carrier Suit 55 wherein the acid is a carboxylic acid. able for generating the inhalable aerosol upon heating. 335. The cartomizer of any one of embodiments 323-333, 322. The use of embodiment 321, wherein a second acid wherein the acid used to form said nicotine Salt is an organic used to form the additional nicotine salt is selected from the acid. group consisting of Salicylic acid, Sorbic acid, benzoic acid, 336. The cartomizer of embodiment 335, wherein the pyruvic acid, lauric acid, and levulinic acid 60 organic acid is monocarboxylic acid, aromatic acid, or keto 323. A cartomizer for an electronic cigarette comprising: acid. a nicotine salt liquid formulation comprising a nicotine salt 337. The cartomizer of embodiment 335, wherein the in a biologically acceptable liquid carrier wherein an organic acid is formic acid, acetic acid, propionic acid, acid used to form said nicotine salt is characterized by butyric acid, Valeric acid, caproic acid, caprylic acid, capric vapor pressure >20 mmHg at 200° C.; 65 acid, citric acid, lauric acid, myristic acid, palmitic acid, an atomizer comprising a heating element in fluid commu Stearic acid, oleic acid, linoleic acid, linolenic acid, pheny nication with the nicotine salt liquid formulation; and lacetic acid, benzoic acid, pyruvic acid, levulinic acid, tartaric US 9,215,895 B2 47 48 acid, lactic acid, malonic acid, Succinic acid, fumaric acid, 362. The cartomizer of embodiment 361, wherein the aero finnaric acid, gluconic acid, Saccharic acid, Salicylic acid, Sol comprises condensate of the nicotine salt. Sorbic acid, malonic acid, or malic acid. 363. The cartomizer of embodiment 361, wherein the aero 338. The cartomizer of any one of embodiments 323-333, Sol comprises condensate of freebase nicotine. wherein the acid used to form the nicotine salt is salicylic 364. The cartomizer of embodiment 361, wherein the aero acid. Sol comprises condensate of freebase nicotine and condensate 339. The cartomizer of any one of embodiments 323-333, of the carrier. wherein the acid used to form the nicotine salt is benzoic acid. 365. The cartomizer of embodiment 361, wherein the aero Sol comprises condensate of freebase nicotine and condensate 340. The cartomizer of any one of embodiments 323-333, 10 of the acid. wherein the acid used to form the nicotine salt is pyruvic acid. 366. The cartomizer of any one of embodiments 361-365, 341. The cartomizer of any one of embodiments 323-333, wherein the aerosol comprises condensate in particle sizes wherein the acid used to form the nicotine salt is sorbic acid. from about 0.1 microns to about 5 microns. 342. The cartomizer of any one of embodiments 323-333, wherein the acid used to form the nicotine salt is lauric acid. 367. The cartomizer of any one of embodiments 361-365, 15 wherein the aerosol comprises condensate in particle sizes 343. The cartomizer of any one of embodiments 323-333, from about 0.1 microns to about 1 or 2 microns. wherein the acid used to form the nicotine salt is levulinic 368. The cartomizer of any one of embodiments 361-365, acid. wherein the aerosol comprises condensate in particle sizes 344. The cartomizer of any one of embodiments 323-333, from about 0.1 microns to about 0.7 microns. wherein said nicotine Salt comprises nicotine pyruvate. 369. The cartomizer of any one of embodiments 361-365, 345. The cartomizer of any one of embodiments 323-333, wherein the aerosol comprises condensate in particle sizes wherein said nicotine Salt comprises nicotine Salicylate. from about 0.3 microns to about 0.4 microns. 346. The cartomizer of any one of embodiments 323-333, 370. The cartomizer of any one of embodiments 361-369, wherein said nicotine Salt comprises nicotine Sorbate. wherein the nicotine salt is in an amount that forms about 347. The cartomizer of any one of embodiments 323-333, 25 0.5% to about 20% nicotine in the inhalable aerosol. wherein said nicotine Salt comprises nicotine laurate. 371. The cartomizer of any one of embodiments 361-369, 348. The cartomizer of any one of embodiments 323-333, wherein the nicotine salt is in an amount that forms about 1% wherein said nicotine Salt comprises nicotine levulinate. to about 20% nicotine in the inhalable aerosol. 349. The cartomizer of any one of embodiments 323-333, 372. The cartomizer of any one of embodiments 323-371, wherein said nicotine Salt comprises nicotine benzoate. 30 wherein the formulation further comprises a flavorant. 350. The cartomizer of any one of embodiments 323-349. 373. The cartomizer of any one of embodiments 323-372, wherein the liquid carrier comprises glycerol, propylene gly wherein the formulation is non-corrosive to an electronic col, trimethylene glycol, water, ethanol or combinations cigarette. thereof. 374. The cartomizer of any one of embodiments 323-373, 351. The cartomizer of any one of embodiments 323-349. 35 wherein the acid is stable at and below operating temperature wherein the liquid carrier comprises propylene glycol and or about 200° C. Vegetable glycerin. 375. The cartomizer of any one of embodiments 323-374, 352. The cartomizer of any one of embodiments 323-349. wherein the acid does not decompose at and below operating wherein the liquid carrier comprises 20% to 50% of propy temperature or about 200° C. lene glycol and 80% to 50% of vegetable glycerin. 40 376. The cartomizer of any one of embodiments 323-375, 353. The cartomizer of any one of embodiments 323-349. wherein the acid does not oxidize at and below operating wherein the liquid carrier comprises 30% propylene glycol temperature or about 200° C. and 70% vegetable glycerin. 377. The cartomizer of any one of embodiments 323-376, 354. The cartomizer of any one of embodiments 323-353, wherein the formulation is non-corrosive to the electronic wherein the liquid formulation has a nicotine concentration of 45 cigarette. about 1% (w/w) to about 25% (w/w). 378. The cartomizer of any one of embodiments 323-377. 355. The cartomizer of any one of embodiments 323-353, wherein the formulation is non-toxic to a user of the elec wherein the liquid formulation has a nicotine concentration of tronic cigarette. about 1% (w/w) to about 20% (w/w). 379. The cartomizer of any one of embodiments 323-378, 356. The cartomizer of any one of embodiments 323-353, 50 wherein the formulation further comprises one or more addi wherein the liquid formulation has a nicotine concentration of tional nicotine salts in a biologically acceptable liquid carrier about 1% (w/w) to about 18% (w/w). Suitable for generating the inhalable aerosol upon heating. 357. The cartomizer of any one of embodiments 323-353, 380. The cartomizer of embodiment 379, whereina second wherein the liquid formulation has a nicotine concentration of acid used to form the additional nicotine salt is selected from about 1% (w/w) to about 15% (w/w). 55 the group consisting of salicylic acid, Sorbic acid, benzoic 358. The cartomizer of any one of embodiments 323-353, acid, pyruvic acid, lauric acid, and levulinic acid. wherein the liquid formulation has a nicotine concentration of 381. An electronic cigarette for generating an inhalable about 4% (w/w) to about 12% (w/w). aerosol comprising 359. The cartomizer of any one of embodiments 323-353, a fluid storage compartment; wherein the liquid formulation has a nicotine concentration of 60 a heater; and about 4% (w/w). a nicotine salt liquid formulation in the fluid storage com 360. The cartomizer of any one of embodiments 323-353, partment, the liquid formulation comprising a nicotine wherein the liquid formulation has a nicotine concentration of salt in a biologically acceptable liquid carrier wherein an about 2% (w/w). acid used to form said nicotine salt is characterized by 361. The cartomizer of any one of embodiments 323-360, 65 vapor pressure >20 mmHg at 200°C.; wherein the electronic cigarette is configured to generate an a battery; and aerosol inhalable by a user. a mouthpiece. US 9,215,895 B2 49 50 382. An electronic cigarette for generating an inhalable 392. The electronic cigarette of embodiment 384, wherein aerosol comprising the operating temperature is from 150° C. to 250° C. a fluid storage compartment; 393. The electronic cigarette of embodiment 384, wherein a heater; and the operating temperature is from 180° C. to 220°C. a nicotine salt liquid formulation in the fluid storage com 394. The electronic cigarette of embodiment 384, wherein partment, the liquid formulation comprising a nicotine the operating temperature is about 200° C. salt in a biologically acceptable liquid carrier wherein an 395. The electronic cigarette of any one of embodiments acid used to form said nicotine salt is characterized by 381-394, wherein the aerosol comprises condensate of the vapor pressure of about 20 to 200 mmHg at 200° C.; nicotine salt. a battery; and 10 396. The electronic cigarette of any one of embodiments a mouthpiece. 381-394, wherein the aerosol comprises condensate of free 383. An electronic cigarette for generating an inhalable base nicotine. aerosol comprising 397. The electronic cigarette of any one of embodiments a fluid storage compartment; 15 381-394, wherein the aerosol comprises condensate of free a heater; and base nicotine and condensate of the carrier. a nicotine salt liquid formulation in the fluid storage com 398. The electronic cigarette of any one of embodiments partment, the liquid formulation comprising a nicotine 381-394, wherein the aerosol comprises condensate of free salt in a biologically acceptable liquid carrier wherein an base nicotine and condensate of the acid. acid used to form said nicotine salt is further character 399. The electronic cigarette of any one of embodiments ized by a melting point <160°C., a boiling point >160° 381 -398, wherein the aerosol comprises condensate in par C., and at least a 50-degree difference between the melt ticle sizes from about 0.1 microns to about 5 microns. ing point and the boiling point; 400. The electronic cigarette of any one of embodiments a battery; and 381 -398, wherein the aerosol comprises condensate in par a mouthpiece. 25 ticle sizes from about 0.1 microns to about 1 or 2 microns. 384. An electronic cigarette for generating an inhalable 401. The electronic cigarette of any one of embodiments aerosol comprising 381 -398, wherein the aerosol comprises condensate in par a fluid storage compartment; ticle sizes from about 0.1 microns to about 0.7 microns. a heater; and 402. The electronic cigarette of any one of embodiments a nicotine salt liquid formulation in the fluid storage com 30 partment, the liquid formulation comprising a nicotine 381 -398, wherein the aerosol comprises condensate in par salt in a biologically acceptable liquid carrier whereinan ticle sizes from about 0.3 microns to about 0.4 microns. acid used to form said nicotine salt is further character 403. The electronic cigarette of any one of embodiments ized by a melting point at least 40 degrees lower than an 381–402, wherein the acid is a carboxylic acid. operating temperature of the electronic cigarette, a boil 35 404. The electronic cigarette of any one of embodiments ing point no more than 40 degrees lower than the oper 381-402, wherein the acid used to form said nicotine salt is an ating temperature of the electronic cigarette, and at least organic acid. a 50-degree difference between the melting point and the 405. The electronic cigarette of embodiment 404, wherein boiling point; the organic acid is monocarboxylic acid, aromatic acid, or a battery; and 40 keto acid. a mouthpiece. 406. The electronic cigarette of embodiment 404, wherein 385. The electronic cigarette of any one of embodiments the organic acid is formic acid, acetic acid, propionic acid, 381-384, wherein the heater comprises a heater chamber, a butyric acid, Valeric acid, caproic acid, caprylic acid, capric fluid wick, and a resistive heating element in contact with the acid, citric acid, lauric acid, myristic acid, palmitic acid, fluid wick. 45 Stearic acid, oleic acid, linoleic acid, linolenic acid, pheny 386. The electronic cigarette of any one of embodiments lacetic acid, benzoic acid, pyruvic acid, levulinic acid, tartaric 381-384, wherein the mouthpiece, the heater and the fluid acid, lactic acid, malonic acid, Succinic acid, fumaric acid, storage compartment form a cartomizer separable from the finnaric acid, gluconic acid, Saccharic acid, salicylic acid, battery. Sorbic acid, malonic acid, or malic acid. 387. The electronic cigarette of any one of embodiments 50 407. The electronic cigarette of any one of embodiments 381-384, wherein the heater and the fluid storage compart 381-402, wherein the acid used to form the nicotine salt is ment form a cartomizer separable from the battery and the salicylic acid. mouthpiece. 408. The electronic cigarette of any one of embodiments 388. The electronic cigarette of any one of embodiments 381-402, wherein the acid used to form the nicotine salt is 381-384, wherein the fluid storage compartment is separable 55 benzoic acid. from the heater, the battery and the mouthpiece. 409. The electronic cigarette of any one of embodiments 389. The electronic cigarette of any one of embodiments 381-402, wherein the acid used to form the nicotine salt is 381-383, wherein the electronic cigarette heats the nicotine pyruvic acid. salt formulation to an operating temperature from 150° C. to 410. The electronic cigarette of any one of embodiments 2500 C. 60 381-402, wherein the acid used to form the nicotine salt is 390. The electronic cigarette of any one of embodiments Sorbic acid. 381-383, wherein the electronic cigarette heats the nicotine 411. The electronic cigarette of any one of embodiments salt formulation to an operating temperature from 180° C. to 381-402, wherein the acid used to form the nicotine salt is 2200 C. lauric acid. 391. The electronic cigarette of any one of embodiments 65 412. The electronic cigarette of any one of embodiments 381-383, wherein the electronic cigarette heats the nicotine 381-402, wherein the acid used to form the nicotine salt is salt formulation to an operating temperature of about 200°C. levulinic acid. US 9,215,895 B2 51 52 413. The electronic cigarette of any one of embodiments 435. The electronic cigarette of any one of embodiments 381–402, wherein said nicotine salt comprises nicotine pyru 381-434, wherein the acid does not decompose at and below Vate. operating temperature or about 200° C. 414. The electronic cigarette of any one of embodiments 436. The electronic cigarette of any one of embodiments 381–402, wherein said nicotine salt comprises nicotine sali 381-435, wherein the acid does not oxidize at and below cylate. operating temperature or about 200° C. 415. The electronic cigarette of any one of embodiments 437. The electronic cigarette of any one of embodiments 381–402, wherein said nicotine salt comprises nicotine sor 381-436, wherein the formulation is non-corrosive to the bate. electronic cigarette. 416. The electronic cigarette of any one of embodiments 10 438. The electronic cigarette of any one of embodiments 381–402, wherein said nicotine salt comprises nicotine lau 381-437, wherein the formulation is non-toxic to a user of the rate. electronic cigarette. 417. The electronic cigarette of any one of embodiments 439. The electronic cigarette of any one of embodiments 381–402, wherein said nicotine salt comprises nicotine levuli 381-438, wherein the formulation further comprises one or nate. 15 more additional nicotine salts in a biologically acceptable 418. The electronic cigarette of any one of embodiments liquid carrier Suitable for generating the inhalable aerosol 381–402, wherein said nicotine salt comprises nicotine ben upon heating. ZOate. 440. The electronic cigarette of embodiment 439, wherein 419. The electronic cigarette of any one of embodiments a second acid used to form the additional nicotine salt is 381-419, wherein the liquid carrier comprises glycerol, pro selected from the group consisting of salicylic acid, Sorbic pylene glycol, trimethylene glycol, water, ethanol or combi acid, benzoic acid, pyruvic acid, lauric acid, and levulinic nations thereof. acid. 420. The electronic cigarette of any one of embodiments 441. A cartridge in an electronic cigarette comprising a 381-419, wherein the liquid carrier comprises propylene gly fluid storage compartment, wherein the fluid storage com col and vegetable glycerin. 25 partment stores a nicotine salt liquid formulation comprising 421. The electronic cigarette of any one of embodiments a nicotine Salt in a biologically acceptable liquid carrier 381-419, wherein the liquid carrier comprises 20% to 50% of wherein an acid used to form said nicotine salt is character propylene glycol and 80% to 50% of vegetable glycerin. ized by vapor pressure >20 mmHg at 200° C. 422. The electronic cigarette of any one of embodiments 442. A cartridge in an electronic cigarette comprising a 381-419, wherein the liquid carrier comprises 30% propylene 30 fluid storage compartment, wherein the fluid storage com glycol and 70% vegetable glycerin. partment stores a nicotine salt liquid formulation comprising 423. The electronic cigarette of any one of embodiments a nicotine salt in a biologically acceptable liquid carrier 381-422, wherein the nicotine salt is in an amount that forms wherein an acid used to form said nicotine salt is character about 0.5% to about 20% nicotine in the inhalable aerosol. ized by vapor pressure of about 20 to 200 mmHg at 200°C. 424. The electronic cigarette of any one of embodiments 35 443. A cartridge in an electronic cigarette comprising a 381-422, wherein the nicotine salt is in an amount that forms fluid storage compartment, wherein the fluid storage com about 1% to about 20% nicotine in the inhalable aerosol. partment stores a nicotine salt liquid formulation comprising 425. The electronic cigarette of any one of embodiments a nicotine Salt in a biologically acceptable liquid carrier 381-424, wherein the liquid formulation has a nicotine con wherein an acid used to form said nicotine salt is further centration of about 1% (w/w) to about 25% (w/w). 40 characterized by a melting point <160° C., a boiling point 426. The electronic cigarette of any one of embodiments >160° C., and at least a 50-degree difference between the 381-424, wherein the liquid formulation has a nicotine con melting point and the boiling point. centration of about 1% (w/w) to about 20% (w/w). 444. A cartridge in an electronic cigarette comprising a 427. The electronic cigarette of any one of embodiments fluid storage compartment, wherein the fluid storage com 381-424, wherein the liquid formulation has a nicotine con 45 partment stores a nicotine salt liquid formulation comprising centration of about 1% (w/w) to about 18% (w/w). a nicotine Salt in a biologically acceptable liquid carrier 428. The electronic cigarette of any one of embodiments wherein an acid used to form said nicotine salt is further 381-424, wherein the liquid formulation has a nicotine con characterized by a melting point at least 40 degrees lower than centration of about 1% (w/w) to about 15% (w/w). an operating temperature of the electronic cigarette, a boiling 429. The electronic cigarette of any one of embodiments 50 point no more than 40 degrees lower than the operating tem 381-424, wherein the liquid formulation has a nicotine con perature of the electronic cigarette, and at least a 50-degree centration of about 4% (w/w) to about 12% (w/w). difference between the melting point and the boiling point. 430. The electronic cigarette of any one of embodiments 445. The cartridge of any one of embodiments 441-444, 381-424, wherein the liquid formulation has a nicotine con wherein the cartridge is separable from the electronic ciga centration of about 4% (w/w). 55 rette. 431. The electronic cigarette of any one of embodiments 446. The cartridge of any one of embodiments 441-445, 381-424, wherein the liquid formulation has a nicotine con wherein the acid is a carboxylic acid. centration of about 2% (w/w). 447. The cartridge of any one of embodiments 441-445, 432. The electronic cigarette of any one of embodiments wherein the acid used to form said nicotine Salt is an organic 381-431, wherein the formulation further comprises a fla 60 acid. VOrant. 448. The cartridge of embodiment 447, wherein the 433. The electronic cigarette of any one of embodiments organic acid is monocarboxylic acid, aromatic acid, or keto 381-432, wherein the formulation is non-corrosive to an elec acid. tronic cigarette. 449. The cartridge of embodiment 447, wherein the 434. The electronic cigarette of any one of embodiments 65 organic acid is formic acid, acetic acid, propionic acid, 381-433, wherein the acid is stable at and below operating butyric acid, Valeric acid, caproic acid, caprylic acid, capric temperature or about 200° C. acid, citric acid, lauric acid, myristic acid, palmitic acid, US 9,215,895 B2 53 54 Stearic acid, oleic acid, linoleic acid, linolenic acid, pheny 474. The cartridge of any one of embodiments 441-473, lacetic acid, benzoic acid, pyruvic acid, levulinic acid, tartaric wherein the formulation is non-corrosive to an electronic acid, lactic acid, malonic acid, Succinic acid, fumaric acid, cigarette. finnaric acid, gluconic acid, Saccharic acid, Salicylic acid, 475. The cartridge of any one of embodiments 441-474, Sorbic acid, malonic acid, or malic acid. wherein the acid is stable at and below operating temperature 450. The cartridge of any one of embodiments 441-445, or about 200° C. wherein the acid used to form the nicotine salt is salicylic 476. The cartridge of any one of embodiments 441-475, acid. wherein the acid does not decompose at and below operating 451. The cartridge of any one of embodiments 441-445, temperature or about 200° C. wherein the acid used to form the nicotine salt is benzoic acid. 10 452. The cartridge of any one of embodiments 441-445, 477. The cartridge of any one of embodiments 441-476, wherein the acid used to form the nicotine salt is pyruvic acid. wherein the acid does not oxidize at and below operating 453. The cartridge of any one of embodiments 441-445, temperature or about 200° C. wherein the acid used to form the nicotine salt is sorbic acid. 478. The cartridge of any one of embodiments 441-477, wherein the formulation is non-corrosive to the electronic 454. The cartridge of any one of embodiments 441-445, 15 wherein the acid used to form the nicotine salt is lauric acid. cigarette. 455. The cartridge of any one of embodiments 441-445, 479. The cartridge of any one of embodiments 441-478, wherein the acid used to form the nicotine salt is levulinic wherein the formulation is non-toxic to a user of the elec acid. tronic cigarette. 456. The cartridge of any one of embodiments 441-445, 480. The cartridge of any one of embodiments 441-479. wherein said nicotine Salt comprises nicotine pyruvate. wherein the formulation further comprises one or more addi 457. The cartridge of any one of embodiments 441-445, tional nicotine salts in a biologically acceptable liquid carrier wherein said nicotine Salt comprises nicotine Salicylate. Suitable for generating the inhalable aerosol upon heating. 458. The cartridge of any one of embodiments 441-445, 481. The cartridge of embodiment 480, wherein a second wherein said nicotine Salt comprises nicotine Sorbate. 25 acid used to form the additional nicotine salt is selected from 459. The cartridge of any one of embodiments 441-445, the group consisting of salicylic acid, Sorbic acid, benzoic wherein said nicotine Salt comprises nicotine laurate. acid, pyruvic acid, lauric acid, and levulinic acid. 460. The cartridge of any one of embodiments 441-445, 482. A kit comprising: wherein said nicotine Salt comprises nicotine levulinate. (a) an electronic cigarette for generating an inhalable aero 461. The cartridge of any one of embodiments 441-445, 30 Sol comprising wherein said nicotine Salt comprises nicotine benzoate. i. a device body comprising a cartridge receptacle; 462. The cartridge of any one of embodiments 441-461, wherein the liquid carrier comprises glycerol, propylene gly ii. a cartridge comprising a fluid storage compartment, col, trimethylene glycol, water, ethanol or combinations wherein the fluid storage compartment stores a nicotine thereof. 35 salt liquid formulation comprising a nicotine salt in a 463. The cartridge of any one of embodiments 441-461, biologically acceptable liquid carrier wherein an acid wherein the liquid carrier comprises propylene glycol and used to form said nicotine salt is characterized by vapor Vegetable glycerin. pressure >20 mmHg at 200° C.; 464. The cartridge of any one of embodiments 441-461, iii. a heater; wherein the liquid carrier comprises 20% to 50% of propy 40 iv. a battery; and lene glycol and 80% to 50% of vegetable glycerin. V. a mouthpiece; and 465. The cartridge of any one of embodiments 441-461, (b) instructions for using the electronic cigarette to gener wherein the liquid carrier comprises 30% propylene glycol ate an inhalable aerosol. and 70% vegetable glycerin. 483. A kit comprising: 466. The cartridge of any one of embodiments 441-465, 45 (a) an electronic cigarette for generating an inhalable aero wherein the liquid formulation has a nicotine concentration of Sol comprising about 1% (w/w) to about 25% (w/w). i. a device body comprising a cartridge receptacle; 467. The cartridge of any one of embodiments 441-465, ii. a cartridge comprising a fluid storage compartment, wherein the liquid formulation has a nicotine concentration of wherein the fluid storage compartment stores a nicotine about 1% (w/w) to about 20% (w/w). 50 salt liquid formulation comprising a nicotine salt in a 468. The cartridge of any one of embodiments 441-465, biologically acceptable liquid carrier wherein an acid wherein the liquid formulation has a nicotine concentration of used to form said nicotine salt is characterized by vapor about 1% (w/w) to about 18% (w/w). pressure of about 20 to 200 mmHg at 200° C.; 469. The cartridge of any one of embodiments 441-465, iii. a heater; wherein the liquid formulation has a nicotine concentration of 55 iv. a battery; and about 1% (w/w) to about 15% (w/w). V. a mouthpiece; and 470. The cartridge of any one of embodiments 441-465, (b) instructions for using the electronic cigarette to gener wherein the liquid formulation has a nicotine concentration of ate an inhalable aerosol. about 4% (w/w) to about 12% (w/w). 484. A kit comprising: 471. The cartridge of any one of embodiments 441-465, 60 (a) an electronic cigarette for generating an inhalable aero wherein the liquid formulation has a nicotine concentration of Sol comprising about 4% (w/w). i. a device body comprising a cartridge receptacle; 472. The cartridge of any one of embodiments 441-465, ii. a cartridge comprising a fluid storage compartment, wherein the liquid formulation has a nicotine concentration of wherein the fluid storage compartment stores a nicotine about 2% (w/w). 65 salt liquid formulation comprising a nicotine salt in a 473. The cartridge of any one of embodiments 441-472, biologically acceptable liquid carrier wherein an acid wherein the formulation further comprises a flavorant. used to form said nicotine salt is further characterized by US 9,215,895 B2 55 56 a melting point <160° C., a boiling point >160° C., and 502. The kit of any one of embodiments 482-501, wherein at least a 50-degree difference between the melting point the liquid carrier comprises glycerol, propylene glycol, trim and the boiling point; ethylene glycol, water, ethanol or combinations thereof. iii. a heater; 503. The kit of any one of embodiments 482-501, wherein iv. a battery; and the liquid carrier comprises propylene glycol and vegetable V. a mouthpiece; and glycerin. (b) instructions for using the electronic cigarette to gener 504. The kit of any one of embodiments 482-501, wherein ate an inhalable aerosol. the liquid carrier comprises 20% to 50% of propylene glycol 485. A kit comprising: and 80% to 50% of vegetable glycerin. (a) an electronic cigarette for generating an inhalable aero 10 505. The kit of any one of embodiments 482-501, wherein Sol comprising the liquid carrier comprises 30% propylene glycol and 70% i. a device body comprising a cartridge receptacle; Vegetable glycerin. ii. a cartridge comprising a fluid storage compartment, 506. The kit of any one of embodiments 482-505, wherein wherein the fluid storage compartment stores a nicotine the liquid formulation has a nicotine concentration of about salt liquid formulation comprising a nicotine Salt in a 15 1% (w/w) to about 25% (w/w). biologically acceptable liquid carrier wherein an acid 507. The kit of any one of embodiments 482-505, wherein used to form said nicotine salt is further characterized by the liquid formulation has a nicotine concentration of about a melting point at least 40 degrees lower than an oper 1% (w/w) to about 20% (w/w). ating temperature of the electronic cigarette, a boiling 508. The kit of any one of embodiments 482-505, wherein point no more than 40 degrees lower than the operating the liquid formulation has a nicotine concentration of about temperature of the electronic cigarette, and at least a 1% (w/w) to about 18% (w/w). 50-degree difference between the melting point and the 509. The kit of any one of embodiments 482-505, wherein boiling point; the liquid formulation has a nicotine concentration of about iii. a heater; 1% (w/w) to about 15% (w/w). iv. a battery; and 25 510. The kit of any one of embodiments 482-505, wherein V. a mouthpiece; and the liquid formulation has a nicotine concentration of about (b) instructions for using the electronic cigarette to gener 4% (w/w) to about 12% (w/w). ate an inhalable aerosol. 511. The kit of any one of embodiments 482-505, wherein 486. The kit of any one of embodiments 482-485, wherein the liquid formulation has a nicotine concentration of about the acid is a carboxylic acid. 30 4% (w/w). 487. The kit of any one of embodiments 482-485, wherein 512. The kit of any one of embodiments 482-505, wherein the acid used to form said nicotine salt is an organic acid. the liquid formulation has a nicotine concentration of about 488. The kit of embodiment 487, wherein the organic acid 2% (w/w). is monocarboxylic acid, aromatic acid, or keto acid. 513. The kit of any one of embodiments 482-512, wherein 489. The kit of embodiment 487, wherein the organic acid 35 the formulation further comprises a flavorant. is formic acid, acetic acid, propionic acid, butyric acid, 514. The kit of any one of embodiments 482-513, wherein Valeric acid, caproic acid, caprylic acid, capric acid, citric the formulation is non-corrosive to an electronic cigarette. acid, lauric acid, myristic acid, palmitic acid, Stearic acid, 515. The kit of any one of embodiments 482-514, wherein oleic acid, linoleic acid, linolenic acid, phenylacetic acid, the acid is stable at and below operating temperature or about benzoic acid, pyruvic acid, levulinic acid, tartaric acid, lactic 40 2000 C. acid, malonic acid. Succinic acid, fumaric acid, finnaric acid, 516. The kit of any one of embodiments 482-515, wherein gluconic acid, saccharic acid, Salicylic acid, Sorbic acid, mal the acid does not decompose at and below operating tempera onic acid, or malic acid. ture or about 200° C. 490. The kit of any one of embodiments 482-485, wherein 517. The kit of any one of embodiments 482-516, wherein the acid used to form the nicotine salt is salicylic acid. 45 the acid does not oxidize at and below operating temperature 491. The kit of any one of embodiments 482-485, wherein or about 200° C. the acid used to form the nicotine salt is benzoic acid. 518. The kit of any one of embodiments 482-517, wherein 492. The kit of any one of embodiments 482-485, wherein the formulation is non-corrosive to the electronic cigarette. the acid used to form the nicotine salt is pyruvic acid. 519. The kit of any one of embodiments 482-518, wherein 493. The kit of any one of embodiments 482-485, wherein 50 the formulation is non-toxic to a user of the electronic ciga the acid used to form the nicotine salt is sorbic acid. rette. 494. The kit of any one of embodiments 482-485, wherein 520. The kit of any one of embodiments 482-519, wherein the acid used to form the nicotine salt is lauric acid. the formulation further comprises one or more additional 495. The kit of any one of embodiments 482-485, wherein nicotine salts in a biologically acceptable liquid carrier Suit the acid used to form the nicotine salt is levulinic acid. 55 able for generating the inhalable aerosol upon heating. 496. The kit of any one of embodiments 482-485, wherein 521. The kit of embodiment 520, wherein a second acid said nicotine Salt comprises nicotine pyruvate. used to form the additional nicotine salt is selected from the 497. The kit of any one of embodiments 482-485, wherein group consisting of Salicylic acid, Sorbic acid, benzoic acid, said nicotine Salt comprises nicotine salicylate. pyruvic acid, lauric acid, and levulinic acid. 498. The kit of any one of embodiments 482-485, wherein 60 522. A cartridge comprising a fluid storage compartment, said nicotine Salt comprises nicotine Sorbate. wherein the fluid storage compartment stores a nicotine salt 499. The kit of any one of embodiments 482-485, wherein liquid formulation comprising a nicotine salt in a biologically said nicotine Salt comprises nicotine laurate. acceptable liquid carrier wherein an acid used to form said 500. The kit of any one of embodiments 482-485, wherein nicotine Salt is characterized by vapor pressure >20 mmHg at said nicotine Salt comprises nicotine levulinate. 65 2000 C. 501. The kit of any one of embodiments 482-485, wherein 523. A cartridge comprising a fluid storage compartment, said nicotine Salt comprises nicotine benzoate. wherein the fluid storage compartment stores a nicotine salt US 9,215,895 B2 57 58 liquid formulation comprising a nicotine salt in a biologically 543. The cartridge of any one of embodiments 523-543, acceptable liquid carrier wherein an acid used to form said wherein the liquid carrier comprises glycerol, propylene gly nicotine salt is characterized by vapor pressure of about 20 to col, trimethylene glycol, water, ethanol or combinations 200 mmHg at 200° C. thereof. 524. A cartridge comprising a fluid storage compartment, 544. The cartridge of any one of embodiments 523-543, wherein the fluid storage compartment stores a nicotine salt wherein the liquid carrier comprises propylene glycol and liquid formulation comprising a nicotine salt in a biologically Vegetable glycerin. acceptable liquid carrier wherein an acid used to form said 545. The cartridge of any one of embodiments 523-543, nicotine salt is further characterized by a melting point <160° wherein the liquid carrier comprises 20% to 50% of propy C., a boiling point >160° C., and at least a 50-degree differ 10 lene glycol and 80% to 50% of vegetable glycerin. ence between the melting point and the boiling point. 546. The cartridge of any one of embodiments 523-543, 525. A cartridge comprising a fluid storage compartment, wherein the liquid carrier comprises 30% propylene glycol wherein the fluid storage compartment stores a nicotine salt and 70% vegetable glycerin. liquid formulation comprising a nicotine salt in a biologically 547. The cartridge of any one of embodiments 523-547, acceptable liquid carrier wherein an acid used to form said 15 wherein the liquid formulation has a nicotine concentration of nicotine Salt is further characterized by a melting point at least about 1% (w/w) to about 25% (w/w). 40 degrees lower than an operating temperature of the elec 548. The cartridge of any one of embodiments 523-547, tronic cigarette, a boiling point no more than 40 degrees lower wherein the liquid formulation has a nicotine concentration of than the operating temperature of the electronic cigarette, and about 1% (w/w) to about 20% (w/w). at least a 50-degree difference between the melting point and 549. The cartridge of any one of embodiments 523-547, the boiling point. wherein the liquid formulation has a nicotine concentration of 526. The cartridge of any one of embodiments 523-526, about 1% (w/w) to about 18% (w/w). wherein the cartridge can be connected to an electronic ciga 550. The cartridge of any one of embodiments 523-547, rette. wherein the liquid formulation has a nicotine concentration of 527. The cartridge of any one of embodiments 523-527, 25 about 1% (w/w) to about 15% (w/w). wherein the acid is a carboxylic acid. 551. The cartridge of any one of embodiments 523-547, 528. The cartridge of any one of embodiments 523-527, wherein the liquid formulation has a nicotine concentration of wherein the acid used to form said nicotine Salt is an organic about 4% (w/w) to about 12% (w/w). acid. 552. The cartridge of any one of embodiments 523-547, 529. The cartridge of embodiment 529, wherein the 30 wherein the liquid formulation has a nicotine concentration of organic acid is monocarboxylic acid, aromatic acid, or keto about 4% (w/w). acid. 553. The cartridge of any one of embodiments 523-547, 530. The cartridge of embodiment 529, wherein the wherein the liquid formulation has a nicotine concentration of organic acid is formic acid, acetic acid, propionic acid, about 2% (w/w). butyric acid, Valeric acid, caproic acid, caprylic acid, capric 35 554. The cartridge of any one of embodiments 523-553, acid, citric acid, lauric acid, myristic acid, palmitic acid, wherein the formulation further comprises a flavorant. Stearic acid, oleic acid, linoleic acid, linolenic acid, pheny 555. The cartridge of any one of embodiments 523-554, lacetic acid, benzoic acid, pyruvic acid, levulinic acid, tartaric wherein the formulation is non-corrosive to an electronic acid, lactic acid, malonic acid, Succinic acid, fumaric acid, cigarette. finnaric acid, gluconic acid, Saccharic acid, Salicylic acid, 40 556. The cartridge of any one of embodiments 523-555, Sorbic acid, malonic acid, or malic acid. wherein the acid is stable at and below operating temperature 531. The cartridge of any one of embodiments 523-527, or about 200° C. wherein the acid used to form the nicotine salt is salicylic 557. The cartridge of any one of embodiments 523-556, acid. wherein the acid does not decompose at and below operating 532. The cartridge of any one of embodiments 523-527, 45 temperature or about 200° C. wherein the acid used to form the nicotine salt is benzoic acid. 558. The cartridge of any one of embodiments 523-557, 533. The cartridge of any one of embodiments 523-527, wherein the acid does not oxidize at and below operating wherein the acid used to form the nicotine salt is pyruvic acid. temperature or about 200° C. 534. The cartridge of any one of embodiments 523-527, 559. The cartridge of any one of embodiments 523-558, wherein the acid used to form the nicotine salt is sorbic acid. 50 wherein the formulation is non-corrosive to the electronic 535. The cartridge of any one of embodiments 523-527, cigarette. wherein the acid used to form the nicotine salt is lauric acid. 560. The cartridge of any one of embodiments 523-559, 536. The cartridge of any one of embodiments 523-527, wherein the formulation is non-toxic to a user of the elec wherein the acid used to form the nicotine salt is levulinic tronic cigarette. acid. 55 561. The cartridge of any one of embodiments 523-560, 537. The cartridge of any one of embodiments 523-527, wherein the formulation further comprises one or more addi wherein said nicotine Salt comprises nicotine pyruvate. tional nicotine salts in a biologically acceptable liquid carrier 538. The cartridge of any one of embodiments 523-527, Suitable for generating the inhalable aerosol upon heating. wherein said nicotine Salt comprises nicotine Salicylate. 562. The cartridge of embodiment 561, wherein a second 539. The cartridge of any one of embodiments 523-527, 60 acid used to form the additional nicotine salt is selected from wherein said nicotine Salt comprises nicotine Sorbate. the group consisting of salicylic acid, Sorbic acid, benzoic 540. The cartridge of any one of embodiments 523-527, acid, pyruvic acid, lauric acid, and levulinic acid. wherein said nicotine Salt comprises nicotine laurate. Although preferred embodiments of the present invention 541. The cartridge of any one of embodiments 523-527, have been shown and described herein, it will be obvious to wherein said nicotine Salt comprises nicotine levulinate. 65 those skilled in the art that such embodiments are provided by 542. The cartridge of any one of embodiments 523-527, way of example only. Numerous variations, changes, and wherein said nicotine Salt comprises nicotine benzoate. substitutions will now occur to those skilled in the art without US 9,215,895 B2 59 60 departing from the invention. It should be understood that inhalable aerosol comprising particle sizes from about various alternatives to the embodiments of the invention 0.1 microns to about 5 microns; described herein can be employed in practicing the invention. c. inhalation of the inhalable aerosol into the user's lungs It is intended that the following embodiments define the scope over a period of about 5 minutes at a rate of about one of the invention and that methods and structures within the 5 inhalation per 30 seconds results in a nicotine plasma scope of these embodiments and their equivalents be covered Tmax from about 3 minto about 8 min; thereby. d. the nicotine concentration is from about 2% (w/w) to about 6% (w/w); What is claimed is: e. the nicotine formulation comprises monoprotonated 1. A method of delivering nicotine to a user comprising 10 deploying an electronic cigarette comprising a nicotine for nicotine; and mulation that comprises nicotine, an acid, wherein the acid f. the acid does not decompose at room temperature and comprises pyruvic acid, salicylic acid, Sorbic acid, lauric acid, does not decompose at the operating temperature of the levulinic acid, or benzoic acid, and a biologically acceptable electronic cigarette. liquid carrier, wherein: 15 13. The method of claim 12, wherein the acid comprises a. the nicotine formulation has a pH between 2.1-6.7: benzoic acid. b. the nicotine concentration is from about 2% (w/w) to 14. The method of claim 13, wherein the nicotine concen about 6% (w/w); tration is about 5% (w/w). c. operation of the electronic cigarette comprises heating at 15. A method of delivering nicotine to a user comprising least a portion of the nicotine formulation to generate an 20 deploying an electronic cigarette comprising a nicotine for inhalable aerosol comprising particle sizes from about mulation comprising nicotine and benzoic acid in a biologi 0.1 microns to about 5 microns; and cally acceptable liquid carrier, wherein: d. inhalation of the inhalable aerosol into the user's lungs a. the nicotine formulation has a pH between 2.1-6.7: over a period of about 5 minutes at a rate of about one b. the nicotine concentration is from about 2% (w/w) to inhalation per 30 seconds results in a nicotine plasma 25 about 6% (w/w); Tmax from about 3 minto about 8 min. c. operation of the electronic cigarette comprises heating at 2. The method of claim 1, wherein the nicotine plasma least a portion of the nicotine formulation to generate an Tmax is from about 3 minto about 7 min, from about 3 minto inhalable aerosol comprising particle sizes from about about 6 min, from about 3 minto about 5 min, from about 3 0.1 microns to about 5 microns; and minto about 4 min, from about 4 minto about 8 min, from 30 d. inhalation of the inhalable aerosol into the user's lungs about 4 minto about 7 min, from about 4 minto about 6 min, over a period of about 5 minutes at a rate of about one from about 4 minto about 5 min, from about 5 minto about 8 inhalation per 30 seconds results in a nicotine plasma min, from about 5 minto about 7 min, from about 5 minto Tmax from about 5 minto about 8 min. about 6 min, from about 6 minto about 8 min, from about 6 16. A cartridge for use with an electronic cigarette com minto about 7 min, from about 7 minto about 8 min, less than 35 prising a fluid compartment configured to be in fluid commu about 8 min, less than about 7 min, less than about 6 min, less nication with a heating element, the fluid compartment com than about 5 min, less than about 4 min, about 8 min, about 7 prising a nicotine formulation that comprises nicotine and an min, about 6 min, about 5 min, about 4 min, or about 3 min. acid, wherein the acid comprises pyruvic acid, salicylic acid, 3. The method of claim 1, wherein the Tmax is determined Sorbic acid, lauric acid, leVulinic acid, or benzoic acid, and a based on at least three independent data sets. 40 biologically acceptable liquid carrier, wherein: 4. The method of claim 1, wherein the Tmax is a range of a. the nicotine formulation has a pH between 2.1-6.7 at least three independent data sets. b. the nicotine concentration is from about 2% (w/w) to 5. The method of claim 1, wherein the Tmax is an about 6% (w/w); averagetta standard deviation of at least three independent c. operation of the electronic cigarette comprises heating at data sets. 45 least a portion of the nicotine formulation to generate an 6. The method of claim 1, wherein the nicotine formulation inhalable aerosol comprising particle sizes from about comprises a nicotine salt comprising nicotine and an acid. 0.1 microns to about 5 microns; and wherein 7. The method of claim 6, wherein nicotine formulation d. inhalation of the inhalable aerosol into the user's lungs comprises monoprotonated nicotine. over a period of about 5 minutes at a rate of about one 8. The method of claim 1, wherein the acid does not decom- 50 inhalation per 30 seconds results in a nicotine plasma pose at room temperature and does not decompose at the Tmax from about 3 minto about 8 min. operating temperature of the electronic cigarette. 17. The cartridge of claim 16, wherein the nicotine plasma 9. The method of claim 1, wherein the acid comprises one Tmax is from about 3 minto about 7 min, from about 3 minto carboxylic acid functional group. about 6 min, from about 3 minto about 5 min, from about 3 10. The method of claim 1, wherein the acid comprises 55 minto about 4 min, from about 4 minto about 8 min, from benzoic acid. about 4 minto about 7 min, from about 4 minto about 6 min, 11. The method of claim 1, wherein the nicotine concen from about 4 minto about 5 min, from about 5 minto about 8 tration is about 5% (w/w). min, from about 5 minto about 7 min, from about 5 minto 12. A method of delivering nicotine to a user comprising about 6 min, from about 6 minto about 8 min, from about 6 deploying an electronic cigarette comprising a nicotine for- 60 minto about 7 min, from about 7 minto about 8 min, less than mulation that comprises nicotine, an acid, wherein the acid about 8 min, less than about 7 min, less than about 6 min, less comprises pyruvic acid, salicylic acid, Sorbic acid, lauric acid, than about 5 min, less than about 4 min, about 8 min, about 7 levulinic acid, or benzoic acid and a biologically acceptable min, about 6 min, about 5 min, about 4 min, or about 3 min. liquid carrier, wherein: 18. The cartridge of claim 16, wherein the Tmax is deter a. the nicotine formulation has a pH between 2.1-6.7 65 mined based on at least three independent data sets. b. operation of the electronic cigarette comprises heating at 19. The cartridge of claim 16, wherein the Tmax is a range least a portion of the nicotine formulation to generate an of at least three independent data sets. US 9,215,895 B2 61 62 20. The cartridge of claim 16, wherein the Tmax is an averagetta standard deviation of at least three independent data sets. 21. The cartridge of claim 16, wherein the nicotine formu lation comprises a nicotine salt comprising nicotine and an 5 acid. 22. The cartridge of claim 21, wherein nicotine formula tion comprises monoprotonated nicotine. 23. The cartridge of claim 21, wherein the acid does not decompose at room temperature and does not decompose at 10 the operating temperature of the electronic cigarette. 24. The cartridge of claim 21, wherein the acid comprises one carboxylic acid functional group. 25. The cartridge of claim 16, wherein the acid comprises benzoic acid. 15 26. The cartridge of claim 16, wherein the nicotine con centration is about 5% (w/w). k k k k k