US 2013.0143956A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0143956A1 Cady et al. (43) Pub. Date: Jun. 6, 2013

(54) LONG-ACTING INJECTABLE MOXIDECTIN (22) Filed: Nov.30, 2012 FORMULATIONS AND NOVEL MOXDECTIN CRYSTAL FORMS Related U.S. Application Data (71) Applicants: Susan Mancini Cady, Yardley, PA (US); (60) Provisional application No. 61/566,336, filed on Dec. Baoqing Ma, Kendall Park, NJ (US); 2, 2011. Robert Clark Chapman, Downingtown, Publication Classification PA (US); Chunhua Yang, Edison, NJ (US); Uday Jain, Plainsboro, NJ (US) (51) Int. Cl. A6IK3I/365 (2006.01) (72) Inventors: Susan Mancini Cady, Yardley, PA (US); (52) U.S. Cl. Baoqing Ma, Kendall Park, NJ (US); CPC ...... A61 K3I/365 (2013.01) Robert Clark Chapman, Downingtown, USPC ...... 514/450; 549/264; 264/145 PA (US); Chunhua Yang, Edison, NJ (US); Uday Jain, Plainsboro, NJ (US) (57) ABSTRACT This invention provides for novel antiparasitic and pesticidal forms of moxidectin, including a long-acting polymeric (73) Assignee: Merial Limited, Duluth, GA (US) implant. The resulting compounds may be used in veterinary compositions which are used in treating, controlling and pre (21) Appl. No.: 13/690,185 Venting of endo- and ectoparasite infections in animals.

Patent Application Publication Jun. 6, 2013 Sheet 1 of 33 US 2013/0143956 A1

FIG. I.

Six: Restivati

Masaaaaaaaaaaaaaaaaaaaaaaaaaaa estivate 83 3

R33

Patent Application Publication Jun. 6, 2013 Sheet 2 of 33 US 2013/0143956 A1

FIG 2A

Conventional DSC of Moxidectin lot SO9060: ... --

; : f; : : ^ ‘s 1119°C f ---. f - “r-. f

a. -: ; Agree 18649°Cs f 2) skirt" ----. - 23.46°C & i 114.31°CY --.-1N 1.64J/g A. e 173.48°C -3. --- - d : 6.91349 f i. : I i . i

: 206.06°C

-2.8-i 25 75 125 175 225 Temperature (°C) Patent Application Publication Jun. 6, 2013 Sheet 3 of 33 US 2013/0143956 A1

FIG. 2B

Conventional DSC of Moxidectin lot S080701 3.3.

; ; : : - f ”ssaaa. : is irs is 34.6°C f - --- 1,561Jg ; Y- --- f \s s 11-78°C f

a. s ---...-- - \ Ny ----r-.2.167J/g f f o A2. --- er 108.13°C :117.10°C ---. ---...--- / w Y/ ---...s. - 2 ses: Y red i s d I

s r t r r y r T •r 25 75 25 75 225 Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 4 of 33 US 2013/0143956 A1

FIG. 3

PRXD of MOxidectin lot S090601

Theta-2Theta deg) Patent Application Publication Jun. 6, 2013 Sheet 5 of 33 US 2013/0143956 A1

FIG. 4 3 - f :

: 193OC shai, Ya-Ye : i e f a -3- f **s- f v-Yas :s ^s. **. 104.15°C 3 d : ------3267/g ... 196.18C vis----. : 7,591.J.g / “r.ris-1-X--- : 108.53°C : i d ; i 200.7°C

2 25: 75 T is r 175 225 T Temperature (°C) Patent Application Publication Jun. 6, 2013 Sheet 6 of 33 US 2013/0143956 A1

FIG. 5 ... --

198OC

2ss s f sc.-si-. 10.7°C / 3. ---. k- 993 186.33°C ? e “--...-3, 19827C A Yale- 114.82°C *::s;12,30J/g Y *:::: * 3. 4.953.3/g173.18°C S-i- f s f t

202.7°C

25 75 125 175 225 Temperature (°C) Patent Application Publication Jun. 6, 2013 Sheet 7 of 33 US 2013/0143956 A1

FIG. 6

'srx & i x.--- f ---. 110.98°C 88.43°C f ------, 1,895J/g

Sik.**x. 20353°C- Y - / 15.39°C-- *x.se: *-3--- 12.68Jig :

73.55°C 7.051Jig

25 75 25 75 225 Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 8 of 33 US 2013/0143956 A1

FIG. 7

&

a. so

- Yale 3) s f Y-a- tec S s a \ Ast 2 Yae ------; **- y A š. e 162.54c ---.S. Y s e 28.3%ig r- - : s C- y i i -. -) Non-reversible Heat Flow ------? Y,\ \ i| - . & ”O.S is92 I ss., - 2 2 S

f--- ...if12.15°C) I'------...-a-ka-i. t A2 i w 17.18Jig s: : 40.5°C 36.2°C W . - 0.8 Non-reversible Heat Flow (W/g) Y

22.84°C s: - - r-ir-i -r r-, -:0 A. 90 40 19C 240 Temperature (C)

FIG. 8

Moxidectin after 190 °C bath

c ------S. 2. s Theta-2Theta (deg) Patent Application Publication Jun. 6, 2013 Sheet 9 of 33 US 2013/0143956 A1

FIG. 9

Moxidectin ot O906O1 035: 30: 025 020: 0. s

005

Wave numbers (cm) Patent Application Publication Jun. 6, 2013 Sheet 10 of 33 US 2013/0143956 A1

FIG 10

Moxidectirot O906O1 i as iv r . v-Y ------is v W.A.A.A.R.'

ot Ososol, he at 185°C

Raman Shift (cm) Patent Application Publication Jun. 6, 2013 Sheet 11 of 33 US 2013/0143956 A1

FIG. 1 1 (1/2)

Patent Application Publication Jun. 6, 2013 Sheet 12 of 33 US 2013/0143956 A1

FIG. I. 1 (2/2)

Patent Application Publication Jun. 6, 2013 Sheet 13 of 33 US 2013/0143956 A1

FIG. 12

FIG. 13

PXRD of Air-dried Moxidectin/MeCH crystals

Theta-2Theta (deg) Patent Application Publication Jun. 6, 2013 Sheet 14 of 33 US 2013/0143956 A1

Temperature (C)

FIG. I.5 88.

21158°C

43.8

s DSC of air-dried moxidectin MeCH crystals

213.66°C

-3.3--- -T- -T --- -- t 25 75 25 175 225 Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 15 of 33 US 2013/0143956 A1

FG 7

***

Patent Application Publication Jun. 6, 2013 Sheet 16 of 33 US 2013/0143956 A1

s: ------:-:- Delta Y -1187.4% \ TGA of air-dried moxidectin/EtOH crystals

.

Temperature (C) Patent Application Publication Jun. 6, 2013 Sheet 17 of 33 US 2013/0143956 A1

FIG. 19

DSC of air-dried moxidectin/EtOH crystals

y f * 8-s-Xs. ------. * ------.

& *- :

:: : 3.2 -

g :

2.8- r y 25 75 125 175

FIG. 20 88: -

Se: DSC of vacuum-dried moxidectin/EtOH crystals

Y . : s - ---. : --- : : ---. ------: ---. - : --- ^. -3.3 :: -r-

2.8 .i y 25 75 125 75 225 Patent Application Publication Jun. 6, 2013 Sheet 18 of 33 US 2013/0143956 A1

Patent Application Publication Jun. 6, 2013 Sheet 19 of 33 US 2013/0143956 A1

Patent Application Publication Jun. 6, 2013 Sheet 20 of 33 US 2013/0143956 A1

FIG. 24

Patent Application Publication Jun. 6, 2013 Sheet 21 of 33 US 2013/0143956 A1

FIG. 25 ------

C - - - - ......

PXRD of air-dried moxidectin/PA crystals

3 - - - . . .

:

Patent Application Publication Jun. 6, 2013 Sheet 22 of 33 US 2013/0143956 A1

TGA of air-dried moxidectin/PA crystals Delta Yc-14.8.76%

FIG. 28

27.9°C 358.3.g

125 75 225 275 Patent Application Publication Jun. 6, 2013 Sheet 23 of 33 US 2013/0143956 A1

FIG. 29 4 :

278.75°C

DSC of vacuum-dried moxidectin/PA

8.

116.68°C 2. “r-...... 11779°C(1) 17.70°C “r...... 264.76°C 44, J/g

3 -i------~~~~~~~~~~~ 25 75 125 175 225 275

Patent Application Publication Jun. 6, 2013 Sheet 24 of 33 US 2013/0143956 A1

FIG. 31

3.

PXRD of air-dried moxidectin/ n-Butanol crystals

38) - ......

s s s s s s

TGA of air-dried noxidectin? n-Butanol crystals

Sri ------... Delta Y = 14.938% . Patent Application Publication Jun. 6, 2013 Sheet 25 of 33 US 2013/0143956 A1

3.3 : s DSC of air-dried moxidectin f n-Butano crystals 3.3 -

21.92* 45, 40.J.g f

t47.32°C

34.83°C 21469C --- is 25

DSC of vacuum-dried moxidectin? n-Butanol crystals at 60 C

- -

8.4 N. ris ? s: y ^ - s - “r----...-r ------8. ------

-8.8 25- is s is 25 Patent Application Publication Jun. 6, 2013 Sheet 26 of 33 US 2013/0143956 A1

FIG 35

PXRD of noxidectin/n-Butano S3 ...... crystals after vacuum drying at 65 °C

se is l's 2i. S 3,

3.3 : : DSC of vacuum-dried moxidectin/n-Butanol crystals at RT : : 65°C 29.57°C

32.84 - : -3.3 ---. 24.78Jig -** am 9 - ---...-- -- . : Ys...--^ ---.” : i y : i

-- : : i : i : : 5 : 88.00°C :

: 232.93C : 33.-- r : 25 75 25 175 225 Patent Application Publication Jun. 6, 2013 Sheet 27 of 33 US 2013/0143956 A1

FIG. 37

: -

: Patent Application Publication Jun. 6, 2013 Sheet 28 of 33 US 2013/0143956 A1

FIG. 39

SS ...... ionioi--oxo TGA of air-dried noxidectin/MCH crystals :

FIG. 40

DSC of air-dried moxidectin/MCH crystals 3.5- / v. ------. * i “r-ra-re--... - -1.8-

25 75 125 75 223 Patent Application Publication Jun. 6, 2013 Sheet 29 of 33 US 2013/0143956 A1

(Y

s &

s: t

- ;

w w s v Patent Application Publication Jun. 6, 2013 Sheet 30 of 33 US 2013/0143956 A1

FIG 42

Patent Application Publication Jun. 6, 2013 Sheet 31 of 33 US 2013/0143956 A1

***********… (~~~~)-g(0- Patent Application Publication Jun. 6, 2013 Sheet 32 of 33 US 2013/0143956 A1

FIG. 44

in Vitro Release of Formulation (75:25 DEG, 0.4 iv) -O-438-148

O 5 10 15 20 25 3O 35 Elapsed Time, days

FIG. 45

-Are Ot OO588-17

O 5 1 O 15 20 25 30 35 ELAPSED TIME (days) Patent Application Publication Jun. 6, 2013 Sheet 33 of 33 US 2013/0143956 A1

1,000

0.100 ovo.

-0-Average Moxidectin Plasma levels

0.010 to------: O 50 1 OO 150 20 250 US 2013/014395.6 A1 Jun. 6, 2013

LONG-ACTING INUECTABLE MOXDECTIN “tune' the polymer/beneficial agent formulation to enable it FORMULATIONS AND NOVEL MOXDECTIN to be stable and to release at the desired rate. CRYSTAL FORMS 0007 As regards treatment and prevention of parasitic infestation, a particularly important class of beneficial agents CROSS-REFERENCE TO RELATED is the macrocyclic lactone, which may be used for treating APPLICATIONS endo- and ectoparasite infections in mammals and birds. 0001. This application claims benefit of U.S. Provisional Compounds that belong to this class include the avermectins Application No. 61/566,336, filed on Dec. 2, 2011, and incor and milbemycins. These compounds are potent antiparasitic porated herein by reference. agents against a wide range of internal and external parasites. Avermectins and milbemycins share the same common FIELD OF THE INVENTION 16-membered macrocyclic lactone ring; however, milbemy cins do not possess the disaccharide Substituent on the 13-po 0002 This invention relates to novel antiparasitic poly sition of the lactone ring. In addition to treating parasitic morphs and Solvates (pseudopolymorphs) of moxidectin, as insects, avermectins and milbemycins are used to treat well as methods for producing same. The novel moxidectin endoparasites, e.g., roundworm infections, in warm-blooded forms may be used in oral, parental or topical veterinary animals. formulations for treating, controlling and preventing of endo 0008. The avermectins may be isolated from the fermen and ectoparasite infections/infestations in mammals, birds or tation broth of an avermectin producing strain of Streptomy fish, such as horses and household pets. The invention further ces avermitilis and derivatives thereof. The production, iso relates to the use of these forms in novel parasiticidal mox lation and structural determination of the avermectins are idectin polymeric formulations, which may be administered documented in Albers-Schonberg, et. al., J. Am. Chem. Soc. to animals, including dogs and cats, for long-acting control of 1981, 103, 4216-4221 and references cited therein. The endoparasites, including heartworms. The present invention description of the morphological characteristics of the culture also relates to methods of controlling release of a beneficial is described in U.S. Pat. No. 4.310,519, which is incorporated agent from a formulation and methods of using the formula herein by reference. tion to administer a beneficial agent to an animal. 0009. The milbemycins are the aglycone derivatives of the BACKGROUND OF THE INVENTION avermectins, such as those described, for example in U.S. Pat. Nos. 4,144.352; 4,791,134; and 6,653,342. A particularly 0003 Animals and humans suffer from endoparasitical important anthelmintic of this family includes moxidectin, as infections including, for example, helminthiasis which is described, for example in U.S. Pat. Nos. 7,348,417; U.S. Pat. most frequently caused by a group of parasitic worms No. 4,900,753: U.S. Pat. No. 4,988,824; U.S. Pat. No. 5,106, described as nematodes or roundworms. These parasites 994: U.S. Pat. No. 7,645,863; and 4,916,154 (and references cause severe economic losses in pigs, sheep, horses, and cattle cited therein). For milbemycins, reference may be made, inter as well as poultry. Other parasites which occur in the gas alia, to Vercruysse, J. and Rew, R. S., editors, Macrocyclic trointestinal tract of animals and humans include Ancylos Lactones in Antiparasitic Therapy, CABI International 2002: toma, Necator, Ascaris, Strongyloides, Trichinella, Capil Campbell, William C., editor, Ivermectin and Abanectin, laria, Toxocara, Toxascaris, Trichuris, Enterobius and Springer-Verlag, 1989; Davies H. G. et al., 1986, Avermec parasites which are found in the blood or other tissues and tins and Milbemycins, Nat. Prod. Rep., 3,87-121, Mrozik H. organs such as filarial worms and the extra intestinal stages of et al., 1983, Synthesis of Milbemycins from Avermectins, Strongyloides, Toxocara and Trichinella. Tetrahedron Lett. 24, 5333-5336, U.S. Pat. No. 4,134,973 0004 Because of bioavailability, efficacy, or dosing con and EPO 677 054. As evidenced by the numerous references, Venience concerns, many beneficial agents are preferably amorphous moxidectin is well-known in the art, but other administered parenterally. Since a recipient could receive Solid forms, including crystalline polymorphs and Solvates/ several dosage forms over a lifetime, it is essential that the hydrates (pseudopolymorphs), have not been described. dosage form leave little or no undesirable residue. Bioerod (0010 U.S. Pat. No. 6,162,820 (to Merial) disclosed long ible polymeric dosage forms are ideally Suited for these appli acting combinations of fipronil and ivermectin (an avermec cations, and provide the additional advantage that drug deliv ery from a single dosage form may effectively treat the tin). disease state for a prolonged period. (0011 U.S. Pat. No. 6,733,767 (to Merck) disclosed a liq 0005 Known bioerodible polymeric controlled release uid polymeric composition for controlled release of epri devices can be generally categorized as either encapsulated nomectin, consisting essentially of the active ingredient, devices or matrix devices. In encapsulated devices, beneficial PLGA, and solvent mixture. The composition forms a depot agent (e.g., drug) is Surrounded by a polymer layer which upon injection into the animal. controls release of the beneficial agent. The beneficial agent (0012 U.S. Pat. No. 6,797,701 (to Pfizer) disclosed aver in a matrix device, however, is dissolved or Suspended in the mectin 13-monosaccharide 5-oxime formulations consisting polymer matrix and diffuses through the matrix, or is released essentially of the active ingredient and glycol ether. in conjunction with the dissolution, disintegration, decompo (0013 U.S. Pat. No. 7,326,428 (to Rutgers University) dis sition, or erosion of the matrix. closed (in its background section) ivermectin encapsulated in 0006 With matrix devices, beneficial agents can be incor PLGA (50:50) microspheres. The subsequent pulsed release porated into the matrix by physical entrapment or are chemi of this agent, in Vivo, was shown to be dependent on the cally bound to the matrix. When exposed to a biological degradation rate of the polymer matrix. environment of use, the polymer matrix dissolves, disinte (0014 US 2004/0241204 (to Martinodet al.) disclosed sus grates, decomposes, or erodes (i.e., degrades) to release ben tained release mini-implants or pellets in combination may eficial agent. Significant experimental effort is required to provide a blood level of ivermectin active preferably 1 to 4 US 2013/014395.6 A1 Jun. 6, 2013 weeks. A list of potential polymers was disclosed, including desolvating amoxidectin. 1.5 butanol Solvate; or B) heating PLGA, polyamino acids, PGS and Biopol. amorphous moxidectin under specific conditions oftempera 0015 Ivermectin was also successfully combined with ture and time. PLGA to produce a biodegradable drug delivery matrix for 0025. A second object of this invention is to provide for use in dogs (Clark et al., AJVR 2004). long-acting moxidectin-containing polymeric formulations, 0016 ProHeart 6 (Pfizer sustained-release moxidectin which are effective in preventing infestation of animals by product) provided moxidectin sterile microspheres, however, endoparasites, including heartworms, for at least several the product was recalled on Sep. 3, 2004 due to adverse months, and up to as long as six months, or more. Also events, including death, thus illustrating the significant chal disclosed are processes for producing the long-acting poly lenge in producing formulations capable of safely delivering meric formulations. In an embodiment, a solution of moX beneficial agents, particularly moxidectin, over long periods idectin, optionally antioxidants including BHT, and poly d of time. lactide-glycolide (from about 75:25 L:G to about 25:75 L:G) 0017. In view of above references, there are several is produced in appropriate solvent, for example methylene examples of macrocyclic lactone “microsphere' formula chloride, and spray dried, followed by extrusion at about 118° tions, as well as “liquid polymer depot-type' formulations, C. In an embodiment, implantable pellets are cut from the but inventors are unaware of any polymeric moxidectin Solid resulting polymer Strands. implant dosage forms as of the filing of this disclosure. 0026. A third object of this invention is to provide for methods of treatment of parasitic infections of animals, which 0.018 All of these documents and references cited therein, comprise treating the infected animal with an effective anti as well as the references cited herein, are expressly incorpo parasitic and anthelmintic amount of the newly described rated by reference. forms of moxidectin or the long-acting polymeric formula 0019. Notwithstanding the excellent progress in antipara tions, or combinations thereof. sitic research, concerns remain with respect to increasingly 0027. It is noted that the invention does not intend to common reports of resistance among veterinary parasites encompass within the scope of the invention any previously (Parasitology 2005, 131, S179-190). Other concerns related disclosed compound, product, process of making the product to potential adverse effects on dung-dwelling insects essen or method of using the product, which meets the written tial for dung degradation have been raised with respect to description and enablement requirements of the USPTO (35 endectocides. Thus, there remains an ongoing need for novel U.S.C. 112, first paragraph) or the EPO (Article 83 of the endectocides and anthelmintic treatments in Veterinary medi EPC), such that the applicant(s) reserve the right and hereby cine. It is an object of this invention to provide novel endec disclose a disclaimer of any previously described product, tocides and anthelmintic compounds and formulations, as method of making the productor process of using the product. well as methods of treatment using Such compounds. That the It is therefore an intention of the invention to not explicitly invention performs as herein described is Surprising, unex cover compounds, products, processes of making products or pected and nonobvious. compounds, or methods of using products or compounds that 0020 All documents cited or referenced herein (“herein are explicitly disclosed in the prior art or whose novelty is cited documents'), and all documents cited or referenced in destroyed by prior art, including without limitation any prior herein cited documents, together with any manufacturers art herein mentioned; and the applicant(s) explicitly reserve instructions, descriptions, product specifications, and product the right to introduce into any claim a disclaimer as to any sheets for any products mentioned herein or in any document previously disclosed compound, product, process of making incorporated by reference herein, are hereby incorporated the product or method of using the product. Specifically, the herein by reference, and may be employed in the practice of compounds of the invention are not intended to encompass the invention. avermectin/milbemycin or previously disclosed derivatives 0021 Citation or identification of any document in this of avermectin/milbemycin. application does not constitute an admission that such docu 0028. These and other embodiments are disclosed or are ment is available as prior art to the present invention. obvious from and encompassed by, the following Detailed Description. SUMMARY OF THE INVENTION BRIEF DESCRIPTION OF THE DRAWINGS 0022. The instant invention provides for, inter alia, novel crystalline forms of moxidectin, which are effective against 0029. The following detailed description, given by way of endo- and ectoparasites that infest warm-blooded animals, examples, but not intended to limit the invention solely to the including humans. Thus, it is an object of the invention to specific embodiments described, may best be understood in describe such novel solid forms. conjunction with the accompanying drawings, in which: 0023. In another aspect, the invention relates to pharma 0030 FIG. 1 depicts a flow diagram summarizing the dis ceutical and/or veterinary compositions and methods of mak closed moxidectin crystal forms and transformations to and ing and using the alternate forms of moxidectin. In one aspect, therefrom; the moxidectin polymorph has a melting point of about 210° 0031 FIG. 2A depicts a DSC of moxidectin (lot S090601, C amorphous form); 0024. In still another aspect, the invention also provides 0032 FIG. 2B depicts a DSC of moxidectin (lot S080701, for methods for producing moxidectin.butanol, moxidec amorphous form); tin. IPA, and moxidectin.ethanol, Solvates from amor 0033 FIG.3 depicts a PRXD of moxidectin (lot S090601, phous moxidectin. In another aspect, the invention relates to amorphous form); methods for preparing the moxidectin polymorph comprising 0034 FIG. 4 depicts a heating-cooling-heating (20-193 the general steps of for example, but not solely, A) rapidly 20-250° C.) DSC cycle of moxidectin (lot S090601): US 2013/014395.6 A1 Jun. 6, 2013

0035 FIG. 5 depicts a heating-cooling-heating (20-198 0064 FIG. 34 presents the DSC of vacuum-dried mox 20-250° C.) DSC cycle of moxidectin (lot S090601); idectin/n-Butanol crystals at 60° C.; 0036 FIG. 6 depicts a heating-cooling-heating (20-220 0065 FIG. 35 presents the PXRD of moxidectin/n-Bu 20-250° C.) DSC cycle of moxidectin (lot S090601); tanol crystals after vacuum drying at 65° C.; 0037 FIG. 7 depicts a MDSC curve of moxidectin (lot 0066 FIG. 36 presents DSC of vacuum-dried moxidectin/ S090601); n-Butanol crystals at RT (moxidectin (n-BuOH)); 0038 FIG.8 depicts an X-Ray Powder Diffraction pattern 0067 FIG. 37 presents Image of Moxidectin crystal (PXRD) of moxidectin (now Form A) after heating at 190° C. recrystallized from methylcyclohexane (moxidectin (Ma)); (lot S090601); 0068 FIG. 38 presents PXRD of air-dried moxidectin/ 0039 FIG. 9 depicts the IR spectra of moxidectin (top: MCH crystals(moxidectin (MCH)); amorphous moxidectin, lot 5090601; bottom: thermally 0069 FIG. 39 presents TGA of air-dried moxidectin/ transformed crystalline moxidectin, Form A); MCH crystals: 0040 FIG. 10 depicts the Raman spectra for moxidectin (0070 FIG. 40 presents DSC of air-driedmoxidectin/MCH (black: amorphous moxidectin, lot S090601; grey: thermally crystals; transformed crystalline moxidectin): (0071 FIG. 41 presents. An overlay of PXRD of air-dried 0041 FIG. 11 presents microscopic images of hot-stage moxidectin/MCH, moxidectin/MeOH and thermal trans moxidectin (lot S090601); formed moxidectin; 0042 FIG. 12 is an image of moxidectin crystal recrystal 0072 FIG. 42 depicts polymeric implants according to the lized from MeOH (moxidectin (MeOH): instant invention; 0043 FIG. 13 presents the PXRD of air-dried moxidectin/ (0073 FIG. 43 depicts heat flow DSC for 2 different poly MeOH crystals (moxidectin.(MeOH): meric implants; 0044 FIG. 14 is a TGA of air-dried moxidectin/MeOH 0074 FIG. 44 presents in vitro release for a long-acting crystals; formulation (Lot 438-148) containing amorphous moxidec tin, 75:25 DLG, 0.4 iv: 004.5 FIG. 15. DSC of air-dried moxidectin/MeOH crys 0075 FIG. 45 presents in vitro release for a long-acting tals; formulation (Lot 588-17) containing crystalline moxidectin 0046 FIG. 16 presents an image of Moxidectin crystal (Form A), 75:25 DLG, 0.4 iv: resulting from recrystallization of (lot S090601) from EtOH 0076 FIG. 46 presents moxidectin plasma levels for (amorphous form): canines implanted with the amorphous moxidectin long-act 0047 FIG. 17 presents the PXRD of air-dried moxidectin/ EtOH crystals(moxidectin (EtOH)); ing formulation. 0048 FIG. 18 presents the TGA of air-dried moxidectin/ DETAILED DESCRIPTION EtOH crystals: 0049 FIG. 19 presents the DSC of air-dried moxidectin/ 0077. The crystal forms of moxidectin of the invention and EtOH crystals: compositions comprising the forms are highly effective for 0050 FIG. 20 presents the DSC of vacuum-dried mox the treatment or prophylaxis of parasites in or on mammals, idectin/EtOH crystals; fish and birds, and in particular, cats, dogs, horses, chickens, 0051 FIG. 21 presents the PXRD of moxidectin/EtOH pigs, sheep and cattle with the aim of ridding these hosts of all crystals after vacuum drying at 95°C.; the parasites commonly encountered by mammals, fish and 0052 FIG. 22 presents the molecular structure of mox birds. idectin/EtOH showing its hydrogen bonding connection; 0078. The compounds and compositions of the invention 0053 FIG. 23 presents a packing diagram showing its are also active against pests that damage agricultural material, porous channels along 100 direction; and may be effectively used to treat and protect plants, crops, 0054 FIG. 24 presents an image of Moxidectin crystal plant propagation material, property containing wood or resulting from recrystallization of (lot S090601)(amorphous) derived from wood, from harmful pests. 0079 Accordingly, the present invention provides meth from IPA(moxidectin.(iProH)); ods for preventing and treating parasites in or on animals, 0055 FIG. 25 presents the PXRD air-dried moxidectin/ comprising administering a parasiticidally effective amount IPA crystals(moxidectin.(iProH)); of a novel moxidectin form to the animal. The invention also 0056 FIG. 26 presents an image of Moxidectin crystal provides a method for combating or controlling pests and for recrystallized from IPA (lot 070201): protecting crops, growing plants, plant propagation material, 0057 FIG. 27 presents the TGA of air-dried moxidectin/ and wood-containing material, or material derived from IPA crystals; wood, from infestation by pests, comprising contacting the 0058 FIG. 28 presents the DSC of air-dried moxidectin/ pests, plants, plant propagation material, or the soil or water IPA crystals; in which the plants is growing, or the wood-containing mate 0059 FIG. 29 presents the DSC of vacuum-dried mox rial or material derived from wood, with a pesticidally effec idectin/IPA crystals; tive amount of the novel moxidectin forms. 0060 FIG. 30 presents an image of Moxidectin crystal 0080. As used herein, the following terms have the mean recrystallized from n-Butanol (moxidectin (n-BuOH)); ings ascribed to them unless specified otherwise. In this dis 0061 FIG.31 presents the PXRD of air-dried moxidectin/ closure and in the claims, terms such as “comprises.” “com n-Butanol crystals(moxidectin (n-BuOH)); prising.” “containing and "having and the like can have the 0062 FIG. 32 presents the TGA of air-dried moxidectin/ meaning ascribed to them in U.S. patent law and can mean n-Butanol crystals; “includes.” “including and the like: “consisting essentially 0063 FIG. 33 presents the DSC of air-dried moxidectin/ of or “consists essentially likewise has the meaning n-Butanol crystals; ascribed in U.S. patent law and the term is open-ended, allow US 2013/014395.6 A1 Jun. 6, 2013

ing for the presence of more than that which is recited so long 4,831,016; 4,855,317; 4,859,657; 4,871,719; 4,873,224: as basic or novel characteristics of that which is recited is not 4,874,749; 4,895,837: 4,906,619, 4,920,148; 4.963,582: changed by the presence of more than that which is recited, 4,973,711; 4,978,677; 5,015,630, 5,023,241, 5,030,622; but excludes prior art embodiments. 5,055,454; 5,055,596; 5,057,499; 5,077,308; 5,089,490; 0081. Unless otherwise specifically noted or apparent by 5,162,363; 5,169,839: 5,208,222: 5,244,879; 5,262,400; context, “active agent” or “active ingredient’ or “therapeutic 5,830,875; 7,250,402; and EPO 214 731, all of which are agent as used in this specification, means moxidectin, incorporated herein by reference in their entirety. It will be including, but not limited to, amorphous, crystalline and Sol appreciated by persons skilled in the art that the order of vate/hydrate forms. synthetic transformations employed may be varied, and will 0082 One embodiment of the second object of the inven depend on factors such as the nature of other functional tion provides a composition useful for the treatment or pre groups present in a particular substrate, the availability of key vention of a parasitic infection in an animal which comprises intermediates, and the protecting group strategy to be an inert carrier and an effective amount of a form of moxidec adopted. tin. 0088. In one embodiment of the invention, the moxidectin forms may be produced according to the procedures Summa rized in FIG. 1. 0089. In another embodiment of the invention, the amor phous moxidectin is converted to the new crystalline form by immersing the moxidectin into an oil bath at 190° C. for about 2 to about 10 minutes, followed by cooling. Amorphous mox idectin may be distinguished from the novel crystalline mox idectin (Polymorph A), for example, by X-ray crystallography (FIG. 2A). 0090. In an embodiment, with increasing temperature, amorphous moxidectin exhibits a glass transition at 115°C., crystallizes at 175°C. to Polymorph A. melts at 206°C., and finally decomposes at 230° C. Molten moxidectin becomes amorphous upon cooling. Moxidectin (lot 090601) crystal lized at 175° C., and moxidectin (lot 080701) did not crystal lize. 0091 Terms used herein will have their customary mean ing in the art unless specified otherwise. The organic moieties mentioned in the definitions of the variables of formula (I) MOXIDECTIN are like the term halogen—collective terms for individual listings of the individual group members. The prefix C-C, indicates in each case the possible number of carbon atoms in 0083. The invention also provides compositions useful for the group. combating or controlling pests and for protecting crops, 0092. The term “animal' is used herein to include all growing plants, plant propagation material, and wood-con mammals, birds and fish and also include all vertebrate ani taining material, or material derived from wood from infes mals, including humans. It also includes an individual animal tation by pests, comprising a pesticidally effective amount of in all stages of development, including embryonic and fetal a form of moxidectin, in combination with an agriculturally Stages. acceptable carrier. 0093. The term “plant propagation material” refers to any 0084. One embodiment of the third object of the invention parts of a plant which are propagable. In general, a plant provides for a method for the treatment or prevention of propagation material includes the product of the ripened parasitic infections/infestations of animals, which comprises ovule of gymnosperm and angiosperm plants which occurs administering an effective amount of a compound of formula after fertilization and some growth within the mother plant (I) to the animal in need thereof. and includes seed, fruits, spurious fruits, infructescences and 0085. In still another embodiment of the invention, a also rhizomes (rootstocks), corms, tubers, bulbs and Scions. method is provided for the treatment or prevention of a para 0094. The term “plant propagation material' is to be sitic infestation at a locus, which comprises administering or understood to denote all the generative parts of the plant Such applying a parasiticidally effective amount of moxidectin, or as seeds and vegetative plant material Such as cuttings and pharmaceutically acceptable salts thereof, to the locus. With tubers (e.g. potatoes), which can be used for the multiplica respect to animal health applications, "locus is intended to tion of the plant. This includes seeds, roots, fruits, tubers, mean a habitat, breeding ground, area, material or environ bulbs, rhizomes, shoots, sprouts and other parts of plants. ment in which a parasite is growing or may grow, including in Seedlings and young plants, which are to be transplanted after or on an animal. germination or after emergence from Soil, may also be I0086) Still further embodiments of the objects of the included. These plant propagation materials may be treated invention will become apparent as described herein. prophylactically with a plant protection compound either at 0087. The forms and solvates of formula (I) are prepared or before planting or transplanting. by the application or adaptation of known methods (i.e. meth 0.095 A pharmaceutically acceptable carrier is selected on ods heretofore used or described in the chemical literature); the basis of the form of the composition which can include or methods described in one or more of U.S. Pat. Nos. 4,199, oral formulations, baits, dietary Supplements, powders, 569; 4,310,519: 4,423,209; 4,427,663; 4,457,920, 4,806,527; shampoos, pastes, concentrated solution, Suspension, micro US 2013/014395.6 A1 Jun. 6, 2013 emulsion and emulsion. Compositions intended for pharma 0101 Dispersible powders and granules suitable for ceutical use may be prepared according to any method known preparation of an aqueous Suspension by the addition of water in the art for the manufacture of pharmaceutical composi provide the active ingredient in admixture with a dispersing tions. Remington—The Science and Practice of Pharmacy or wetting agent, Suspending agent and one or more preser (21 Edition) (2005), Goodman & Gilman's The Pharmaco Vatives. Suitable dispersing or wetting agents and Suspending logical Basis of Therapeutics (11" Edition) (2005) and agents are exemplified by those already mentioned above. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Additional excipients, for example, Sweetening, bittering, Systems (8' Edition), edited by Allen et al., Lippincott Will flavoring and coloring agents, may also be present. iams & Wilkins, (2005). Syrups and elixirs may be formulated with Sweetening 0096. The composition of the invention can be in a variety agents, for example, glycerol, propylene glycol, Sorbitol or of forms which include, but are not limited to, oral formula Sucrose. Such formulations may also contain a demulcent, a tions, injectable formulations, and topical, dermal or Subder preservative, flavoring agent(s) and/or coloring agent(s). mal formulations. 0102. In another embodiment of the invention, the com 0097. The composition of the invention may be in a form position can be in paste form. Examples of embodiments in a Suitable for oral use, for example, as baits (see, e.g., U.S. Pat. paste form include but are not limited to those described in No. 4,564,631 incorporated herein by reference), dietary U.S. Pat. Nos. 6,787,342 and 7,001,889, both of which are Supplements, troches, lozenges, chewables, tablets, hard or incorporated herein by reference. In addition to the active Soft capsules, emulsions, aqueous or oily suspensions, aque agent of the invention, the paste can also contain fumed silica; ous or oily Solutions, oral drench formulations, dispersible a viscosity modifier, a carrier, optionally, an absorbent; and powders or granules, syrups or elixirs, enteric formulations or optionally, a colorant, stabilizer, Surfactant, or preservative. pastes. Compositions intended for oral use may be prepared 0103) The process for preparing a paste formulation typi according to any method known in the art for the manufacture cally comprises the steps of of pharmaceutical compositions and Such compositions may (a) dissolving or dispersing the active agent into the carrier by contain one or more agents selected from the group consisting mixing: of Sweetening agents, bittering agents, flavoring agents, col (b) adding the fumed silica to the carrier containing the dis oring agents and preserving agents in order to provide phar Solved active agent compound and mixing until the silica is maceutically elegant and palatable preparations. dispersed in the carrier; 0098 Tablets may contain the active ingredient in admix (c) allowing the intermediate formed in (b) to settle for a time ture with non-toxic, pharmaceutically acceptable excipients sufficient in order to allow the air entrapped during step (b) to which are suitable for the manufacture of tablets. These escape; and excipients may be, for example, inert diluents, such as cal cium carbonate, sodium carbonate, lactose, calcium phos (d) adding the viscosity modifier to the intermediate with phate or sodium phosphate; granulating and disintegrating mixing to produce a uniform paste. agents, for example, corn starch, or alginic acid; binding 0104. The above steps are illustrative, but not limiting. For agents, for example starch, gelatin or acacia, and lubricating example, step (a) can be the last step. agents, for example, magnesium Stearate, Stearic acid or talc, 0105. In one embodiment of the formulation, the formu the tablets may be uncoated or they may be coated by known lation is a paste containing the active agent compound, fumed techniques to delay disintegration and absorption in the gas silica, a viscosity modifier, an absorbent, a colorant; and a trointestinal tract and thereby provide a Sustained action over hydrophilic carrier which is a triacetin, a monoglyceride, a a longer period. For example, a time delay material Such as diglyceride, or a triglyceride. glyceryl monostearate or glyceryl distearate may be 0106 The paste may also include a viscosity modifier employed. They may also be coated by the technique including, but not limited to, polyethylene glycols (PEG) described in U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265, such as PEG 200, PEG 300, PEG 400, PEG 600; monoetha 874, all of which are incorporated herein by reference, to form nolamine, triethanolamine, glycerol, propylene glycol, poly osmotic therapeutic tablets for controlled release. oxyethylene (20) sorbitan mono-oleate (polysorbate 80 or 0099 Formulations for oral use may be hard gelatin cap TWEEN 80), and polyoxamers (e.g., PLURONIC L81); an Sules, wherein the active ingredient is mixed with an inert absorbent selected from the group consisting of magnesium Solid diluent, for example, calcium carbonate, calcium phos carbonate, calcium carbonate, starch, and cellulose and its phate or kaolin. Capsules may also be soft gelatin capsules, derivatives. wherein the active ingredient is mixed with water or miscible 0107 Colorants may be added to the inventive formula Solvents such as propylene glycol, PEGs and ethanol, oran oil tions. Colorants contemplated by the present invention are medium, for example peanut oil, liquid paraffin, or olive oil. those commonly known in the art. Specific colorants include, 0100. The compositions of the invention may also be in the for example, dyes, FD&C Blue #1 Aluminum Lake, caramel, form of oil-in-water or water-in-oil emulsions. The oily phase colorant based upon iron oxide or a mixture of any of the maybe a vegetable oil, for example, olive oil or arachis oil, or foregoing. Especially preferred are organic dyes and titanium a mineral oil, for example, liquid paraffin or mixtures of these. dioxide. Preferred ranges include from about 0.5% to about Suitable emulsifying agents may be naturally-occurring 25%. phosphatides, for example, soybean, lecithin, and esters or 0108. As vehicle or diluent, mention may be made of plant partial esters derived from fatty acids and hexitol anhydrides, oils such as, but not limited to Soybean oil, groundnut oil, for example, Sorbitan monoleate, and condensation products castor oil, corn oil, cotton oil, olive oil, grape seed oil, Sun of the said partial esters with ethylene oxide, for example, flower oil, etc.; mineral oils such as, but not limited to, pet polyoxyethylene Sorbitan monooleate. The emulsions may rolatum, paraffin, silicone, etc.; aliphatic or cyclic hydrocar also contain Sweetening agents, bittering agents, flavoring bons or alternatively, for example, medium-chain (Such as C8 agents, and/or preservatives. to C12) triglycerides. US 2013/014395.6 A1 Jun. 6, 2013

0109. In another embodiment of the invention, an emol the active material in the main solvent and then the other lient and/or spreading and/or film-forming agent will be ingredients or adjuvants are added. added. One embodiment of the emollient and/or spreading 0115 Additionally, the inventive formulations may con and/or film-forming agents are those agents selected from the tain other inert ingredients such as antioxidants, preserva group consisting of tives, or pH stabilizers. These compounds are well known in (a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of the formulation art. Antioxidant such as an alpha tocopherol, vinyl acetate and vinylpyrrolidone, polyethylene glycols, ascorbic acid, ascorbyl palmitate, fumaric acid, malic acid, benzyl alcohol, mannitol, glycerol, Sorbitol, polyoxyethyl Sodium ascorbate, Sodium metabisulfate, n-propyl gallate, enated Sorbitan esters; lecithin, Sodium carboxymethylcellu BHA (butylated hydroxy anisole), BHT (butylated hydroxy lose, silicone oils, polydiorganosiloxane oils (such as poly toluene) monothioglycerol and the like, may be added to the dimethylsiloxane (PDMS) oils), for example those present formulation. The antioxidants are generally added to containing silanol functionalities, or a 45V2 oil, the formulation in amounts of from about 0.01 to about 2.0%, (b) anionic Surfactants such as alkaline Stearates, sodium, based upon total weight of the formulation, with about 0.05 to potassium or ammonium Stearates; calcium Stearate, trietha about 1.0% being especially preferred. Preservatives, such as nolamine Stearate; sodium abietate; alkyl Sulphates (e.g. the parabens (methylparaben and/or propylparaben), are Suit Sodium lauryl Sulphate and Sodium cetyl Sulphate); sodium ably used in the formulation in amounts ranging from about dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; 0.01 to about 2.0%, with about 0.05 to about 1.0% being fatty acids (e.g. those derived from coconut oil), especially preferred. Other preservatives include benzalko (c) cationic Surfactants such as water-soluble quaternary nium chloride, benzethonium chloride, benzoic acid, benzyl ammonium salts of formula N'R"R"R"R"Y, in which the R alcohol, bronopol, butylparaben, cetrimide, chlorhexidine, radicals are optionally hydroxylated hydrocarbon radicals chlorobutanol, chlorocresol, cresol, ethylparaben, imidurea, and Y is an anion of a strong acid Such as the halide, Sulphate methylparaben, phenol, phenoxyethanol, phenylethyl alco and Sulphonate anions; cetyltrimethylammonium bromide is hol, phenylmercuric acetate, phenylmercuric borate, phe among the cationic Surfactants which can be used, nylmercuric nitrate, potassium Sorbate, Sodium benzoate, (d) amine salts of formula N'R"R"R" in which the R radicals Sodium propionate, Sorbic acid, thimerosal, and the like. Pre are optionally hydroxylated hydrocarbon radicals; octadecy ferred ranges for these compounds include from about 0.01 to lamine hydrochloride is among the cationic Surfactants which about 5%. can be used, 0116 Compounds which stabilize the pH of the formula (e) nonionic surfactants such as sorbitan esters, which are tion are also contemplated. Again, such compounds are well optionally polyoxyethylenated (e.g. polysorbate 80), poly known to a practitioner in the art as well as how to use these oxyethylenated alkyl ethers; polyoxypropylated fatty alco compounds. Buffering systems include, for example, systems hols such as polyoxypropylene-styrol ether, polyethylene selected from the group consisting of acetic acid/acetate, glycol Stearate, polyoxyethylenated derivatives of castor oil, malic acid/malate, citric acid/citrate, tartaric acid/tartrate, polyglycerol esters, polyoxyethylenated fatty alcohols, poly lactic acid/lactate, phosphoric acid/phosphate, glycine/glyci oxyethylenated fatty acids, copolymers of ethylene oxide and mate, tris, glutamic acid/glutamates and Sodium carbonate. propylene oxide, Preferred ranges for pH include from about 4 to about 6.5. (f) amphoteric Surfactants such as the Substituted lauryl com 0117. In one embodiment of the invention, the active agent pounds of betaine, and is present in the formulation at a concentration of about 0.05 to about 60% (w/v). In another embodiment of the invention, (g) a mixture of at least two of these agents. the active agent is present in the formulation as a concentra 0110. The solvent will be used in proportion with the tion from about 1 to about 50% or about 35 to about 50% concentration of the active agent compound and its solubility (w/v). In yet another embodiment of the invention, the active in this solvent. Typically, it will be sought to have the lowest agent is present in the formulation as a concentration from possible volume. The vehicle makes up the difference to about 50% (w/v). In still another embodiment of the inven 100%. tion, the active agent is present in the formulation as a con 0111. In one embodiment of the amount of emollient, the centration about 35% (w/v), about 45% (w/v) or about 50% emollient may be used in a proportion of from about 0.1 to (w/v). about 10%, and about 0.25 to about 5%, by volume. 0118. In one embodiment of the invention, the active agent 0112 The formulation can also comprise an antioxidizing is present in the formulation at a concentration of about 0.05 agent intended to inhibit oxidation in air, this agent typically to 10% weight/volume. In another embodiment of the inven being present in a proportion of about 0.005 to about 1% tion, the active agent is present in the formulation as a con (w/v), and about 0.01 to about 0.05% (w/v) being specially centration from about 0.1 to 2% weight/volume. In yet preferred. another embodiment of the invention, the active agent is 0113. In one embodiment of the antioxidizing agents, the present in the formulation as a concentration from about 0.25 agents are those conventional in the art and include, but are to about 1.5% weight/volume. In still another embodiment of not limited to, butylated hydroxyanisole, butylated hydroxy the invention, the active agent is present in the formulation as toluene, ascorbic acid, Sodium metabisulphite, propyl gallate, a concentration about 1% weight/volume. sodium thiosulphate or a mixture of not more than two of 0119 The composition containing the active agent of the them. invention may be administered continuously, for treatment or 0114. The formulation adjuvants are well known to the prophylaxis, by known methods. Generally, a dose of from practitioner in this art and may be obtained commercially or about 0.001 to about 100 mg per kg of body weight given as through known techniques. These concentrated compositions a single dose or in divided doses, for a period of days, weeks, are generally prepared by simple mixing of the constituents as or months, though higher or lower dosage ranges are indi defined above. Advantageously, the starting point is to mix cated, and such are within the scope of this invention. It is well US 2013/014395.6 A1 Jun. 6, 2013

within the routine skill of the practitioner to determine a nary Manual, 9" Edition, (January 2005)) including, but are particular dosing regimen for a specific host and parasite. not limited to, acarbose, acepromazine maleate, acetami 0120 In one embodiment, the treatment is carried out so as nophen, acetazolamide, acetazolamide Sodium, acetic acid, to administer to the animal, on a single occasion, a dose acetohydroxamic acid, acetylcysteine, acitretin, acyclovir, containing between about 0.001 and about 100 mg/kg of the albendazole, albuterol, alfentanil, allopurinol, alprazolam, active agent. altrenogest, amantadine, amikacin, aminocaproic acid, ami 0121. In another embodiment, the treatment is via a direct nopentamide hydrogen Sulfate, aminophylline/theophylline, topical administration Such as a paste, pour-on, ready-to-use, amiodarone, amitraz, amitriptyline, amlodipine besylate, spot-on, etc. type formulation. Higher amounts may be pro ammonium chloride, ammonium molybdenate, amoxicillin, vided for very prolonged release in or on the body of the amoxicillin, clavulanate potassium, amphotericin B desoxy animal. In another embodiment, the amount of the active cholate, amphotericin B lipid-based, amplicillin, amprolium, ingredient for birds and animals which are Small in size is antacids (oral), antivenin, apomorphione, apramycin Sulfate, greater than about 0.01 mg/kg, and in another embodiment ascorbic acid, asparaginase, aspiring, atenolol, atipamezole, for the treatment of small sized birds and animals, the amount atracurium besylate, atropine Sulfate, aurnofin, aurothioglu of the active agent is between about 1 and about 100 mg/kg of cose, azaperone, azathioprine, azithromycin, baclofen, bar weight of animal. bituates, benazepril, betamethasone, bethanechol chloride, 0122. Other routes of administration include paste, chew bisacodyl, bismuth subsalicylate, bleomycin, boldenone able, and gel formulations. undecylenate, bromides, bromocriptine mesylate, budenos 0123. The solid forms of the invention can be formulated ide, buprenorphine, buspirone, buSulfan, butorphanol tar in various ways, depending on the prevailing biological and/ trate, cabergoline, calcitonin Salmon, calcitrol, calcium salts, or chemico-physical parameters. Examples of possible for captopril, carbenicillin indanyl sodium, carbimazole, carbo mulations are: wettable powders (WP), water-soluble pow platin, carnitine, carprofen, carvedilol, cefadroxil, cefazolin ders (SP), water-soluble concentrates, emulsifiable Sodium, cefixime, cefoperaZone sodium, cefotaxime Sodium, concentrates (EC), emulsions (EW) such as oil-in-water and cefotetan disodium, cefoxitin Sodium, cefpodoxime proxetil, water-in-oil emulsions, Suspension concentrates (SC), dis ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, persions on an oil or water basis, capsule Suspensions (CS), cephalexin, cephalosporins, cephapirin, charcoal (activated), dusts (DP), seed-dressing products, granules for broadcasting chlorambucil, chloramphenicol, chlordiazepoxide, chlor and soil application, granules (GR) in the form of microgran diazepoxide--/-clidinium bromide, chlorothiazide, chlorphe ules, spray granules, coated granules and adsorption gran niramine maleate, chlorpromazine, chlorpropamide, chlo ules, water-dispersible granules (WG), water-soluble gran rtetracycline, chorionic gonadotropin (HCG), chromium, ules (SG), ULV formulations, microcapsules and waxes. cimetidine, ciprofloxacin, cisapride, cisplatin, citrate salts, 0.124. These individual formulation types are known in clarithromycin, clemastine fumarate, clenbuterol, clindamy principle and described, for example, in: Winnacker-Kichler, cin, clofazimine, clomipramine, claonazepam, clonidine, clo “Chemische Technologie” Chemical Technology, Volume prostenol Sodium, cloraZepate dipotassium, clorSulon, clox 7, C. Hauser Verlag, Munich, 4th Edition 1986; Wade van acillin, codeine phosphate, colchicine, corticotropin Valkenburg, “Pesticide Formulations', Marcel Dekker, N.Y., (ACTH), cosyntropin, cyclophosphamide, cyclosporine, 1973; K. Martens, “Spray Drying Handbook'', 3rd Ed. 1979, cyproheptadine, cytarabine, dacarbazine, dactinomycin/acti G. Goodwin Ltd. London. nomycin D, dalteparin Sodium, danazol, dantrolene Sodium, 0.125. The necessary formulation auxiliaries such as inert dapsone, decoquinate, deferoxamine mesylate, deracoxib, materials, Surfactants, solvents and other additives are also deslorelin acetate, desmopressin acetate, desoxycorticoster known and described, for example, in: Watkins, “Handbook one pivalate, detomidine, dexamethasone, dexpanthenol, of Insecticide Dust Diluents and Carriers', 2nd Ed., Darland dexraaZOxane, dextran, diazepam, diazoxide (oral), dichlor Books, Caldwell N.J.; H.V. Olphen, “Introduction to Clay phenamide, dichlorvos, diclofenac sodium, dicloxacillin, Colloid Chemistry, 2nd Ed., J. Wiley & Sons, N.Y.: C. Mars diethylcarbamazine citrate, diethylstilbestrol (DES), difloxa den, “Solvents Guide', 2nd Ed., Interscience, N.Y. 1963: cin, digoxin, dihydrotachysterol (DHT), diltiazem, dimenhy McCutcheon’s “Detergents and Emulsifiers Annual, MC drinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprost Publ. Corp., Ridgewood N.J.; Sisley and Wood, “Encyclope tromethamine, diphenylhydramine, disopyramide phosphate, dia of Surface Active Agents”, Chem. Publ. Co. Inc., N.Y. dobutamine, docusate/DSS. dolasetron mesylate, domperi 1964; Schönfeldt, “Grenzfláchenaktive Athylenoxidad done, dopamine, doramectin, doxapram, doxepin, doxorubi dukte'. Surface-active ethylene oxide adducts, Wiss. Ver cin, doxycycline, edetate calcium disodium.calcium EDTA, lagsgesell. Stuttgart 1976: Winnacker-Kichler, “Chemische edrophonium chloride, enalapril/enalaprilat, enoxaparin Technologie” Chemical Technology, Volume 7, C. Hauser Sodium, enrofloxacin, ephedrine Sulfate, epinephrine, epo Verlag, Munich, 4th Ed. 1986. etin/erythropoietin, eprinomectin, epsiprantel, erythromycin, 0126. Additional pharmaceutical active agents may be esmolol, estradiol cypionate, ethacrynic acid/ethacrynate used in the compositions of the invention. Active agents Sodium, ethanol (alcohol), etidronate sodium, etodolac, eto include pesticidally or veterinarily active ingredients, which midate, euthanasia agents w/pentobarbital, famotidine, fatty include, but are not limited to, acaricides, anthelmintics, anti acids (essential/omega), felbamate, fenbendazole, fentanyl. parasitics and insecticides, may also be added to the compo ferrous sulfate, filgrastim, finasteride, fipronil, florfenicol, sitions of the invention. Anti-parasitic agents can include both fluconazole, flucytosine, fludrocortisone acetate, flumazenil. ectoparasiticidal and endoparasiticidal agents. flumethasone, flunixin meglumine, fluorouracil (5-FU), flu 0127. Other active agents that are well-known in the art oxetine, fluticaSone propionate, fluvoxamine maleate, fome may be used in the compositions of the invention (see e.g. pizole (4-MP), furazolidone, furosemide, gabapentin, gem Plumb' Veterinary Drug Handbook, 5' Edition, ed. Donald citabine, gentamicin Sulfate, glimepiride, glipizide, C. Plumb, Blackwell Publishing, (2005) or The Merck Veteri glucagon, glucocorticoid agents, glucosamine/chondroitin US 2013/014395.6 A1 Jun. 6, 2013

Sulfate, glutamine, glyburide, glycerine (oral), glycopyrro racycline, thiabendazole, thiacetarsamide Sodium, thiamine, late, gonadorelin, grisseofulvin, guaifenesin, halothane, thioguanine, thiopental Sodium, thiotepa, thyrotropin, tiamu hemoglobin glutamer-200 (OXYGLOBINR), heparin, lin, ticarcilin disodium, tiletamine/Zolazepam, tilmocsin, tio hetastarch, hyaluronate sodium, hydrazaline, hydrochlorothi pronin, tobramycin Sulfate, tocamide, tolaZoline, telfenamic azide, hydrocodone bitartrate, hydrocortisone, hydromor acid, topiramate, tramadol, trimcinolone acetonide, trientine, phone, hydroxyurea, hydroxyZine, ifosfamide, imidacloprid, triloStane, trimepraxine tartrate w/prednisolone, tripelen imidocarb dipropinate, impenemi-cilastatin Sodium, imi namine, tylosin, urdosiol, Valproic acid, Vanadium, Vancomy pramine, inaminone lactate, insulin, interferon alfa-2a (hu cin, vasopressin, Vecuronium bromide, Verapamil, vinblas man recombinant), iodide (sodium/potassium), ipecac tine sulfate, Vincristine sulfate, vitamin E/selenium, warfarin (syrup), ipodate sodium, iron dextran, isoflurane, isoproter Sodium, Xylazine, yohimbine, Zafirlukast, Zidovudine (AZT), enol, isotretinoin, isoXSuprine HCl, itraconazole, ivermectin, Zinc acetate/zinc sulfate, Zonisamide and mixtures thereof. kaolin?pectin, ketamine, ketoconazole, ketoprofen, ketorolac I0128. In one embodiment of the invention, arylpyrazole tromethamine, lactulose, leuprolide, levamisole, levetirac compounds Such as phenylpyrazoles, e.g. fipronil, are known etam, levothyroxine sodium, lidocaine, lincomycin, liothyro in the art and are suitable for combination with the com nine sodium, lisinopril, lomustine (CCNU), lufenuron, pounds of the invention. Examples of such arylpyrazole com lysine, magnesium, mannitol, marbofloxacin, mechlore pounds include but are not limited to those described in U.S. thamine, meclizine, meclofenamic acid, medetomidine, Pat. Nos. 6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174, medium chain triglycerides, medroxyprogesterone acetate, 540; 6,685,954 and 6,998,131 (each assigned to Merial, Ltd., megestrol acetate, melarsomine, melatonin, meloxican, mel Duluth, Ga.). phalan, meperidine, mercaptopurine, meropenem, met 0129. In another embodiment of the invention, one or formin, methadone, methazolamide, methenamine mande more macrocyclic lactone(s) (in addition to the moxidectin) late?hippurate, methimazole, methionine, methocarbamol. that are described above, which act as an acaricide, anthelm methohexital sodium, methotrexate, methoxyflurane, meth intic agent and insecticide, can be added to the compositions ylene blue, methylphenidate, methylprednisolone, metoclo of the invention. The macrocyclic lactones include, but are pramide, metoprolol, metronidaxole, mexiletine, miboler not limited to, avermectins, such as abamectin, dimadectin, lone, midazolam milbemycin oxime, mineral oil, doramectin, emamectin, eprinomectin, ivermectin, latidectin, minocycline, misoprostol, mitotane, mitoxantrone HCl, mor lepimectin, selamectin, ML-1,694,554 and milbemycins, antel tartrate, morphine Sulfate, moxidectin, naloxone, man Such as milbemectin, milbemycin D, and nemadectin. Also drolone decanoate, naproxen, narcotic (opiate) agonist anal included are the 5-oxo and 5-oxime derivatives of said aver gesics, neomycin Sulfate, neostigmine, niacinamide, mectins and milbemycins. Examples of combinations of nitaZoxanide, nitenpyram, nitrofurantoin, nitroglycerin, arylpyrazole compounds with macrocyclic lactones include nitroprusside sodium, nizatidine, novobiocin Sodium, nysta but are not limited to those described in U.S. Pat. Nos. 6,426, tin, octreotide acetate, olsalazine Sodium, omeproZole, 333; 6,482.425; 6,962,713 and 6,998,131 (all incorporated ondansetron, opiate antidiarrheals, orbifloxacin, oxacillin herein by reference—each assigned to Merial, Ltd., Duluth, Sodium, oxazepam, Oxfendazole, oxibutynin chloride, oxy Ga.). morphone, oxytretracycline, oxytocin, pamidronate diso 0.130. In another embodiment of the invention, the class of dium, pancreplipase, pancuronium bromide, paromomycin acaricides or insecticides known as insect growth regulators Sulfate, paroZetine, pencillamine, general information peni (IGRs) can also be added to the compositions of the invention. cillins, penicillin G, penicillin V potassium, pentazocine, Compounds belonging to this group are well known to the pentobarbital sodium, pentosan polysulfate sodium, pentoxi practitioner and represent a wide range of different chemical fylline, pergolide mesylate, phenobarbital, phenoxyben classes. These compounds all act by interfering with the Zamine, pheylbutaZone, phenylephrine, pheny propanola development or growth of the insect pests. Insect growth mine, phenyloin Sodium, pheromones, parenteral phosphate, regulators are described, for example, in U.S. Pat. Nos. 3,748, phytonadione/vitamin K-1, pimobendan, piperazine, pirli 356, 3,818,047, 4,225,598, 4,798,837, 4,751,225, EP 0179 mycin, piroXicam, polysulfated glycosaminoglycan, pona 022 or U.K. 2140010 as well as U.S. Pat. Nos. 6,096,329 and Zuril, potassium chloride, pralidoxime chloride, praziquantel, 6,685,954 (all incorporated herein by reference, both prazosin, prednisolone/prednisone, primidone, procaina assigned to Merial Ltd., Duluth, Ga.). Examples of IGRs mide, procarbazine, prochlorperazine, propantheline bro suitable for use include but are not limited to methoprene, mide, propionibacterium acnes injection, propofol, propra pyriproxyfen, hydroprene, cyromazine, fluaZuron, lufenuron, nolol, protamine Sulfate, pseudoephedrine, psyllium novaluron, pyrethroids, formamidines and 1-(2, 6-difluo hydrophilic mucilloid, pyrantel pamoate, pyridostigmine robenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea. bromide, pyrilamine maleate, pyrimethamine, quinacrine, I0131. In yet another embodiment of the invention, adulti quinidine, ranitidine, rifampin, S-adenosyl-methionine cide insecticides and acaricides can also be added to the (SAMe), Saline/hyperosmotic laxative, Selamectin, sel composition of the invention. These include pyrethrins egiline? 1-deprenyl, Sertraline, sevelamer, sevoflurane, sily (which include cinerin I, cinerin II, jasmolin I, jasmolin II, marin/milk thistle, sodium bicarbonate, sodium polystyrene pyrethrin I, pyrethrin II and mixtures thereof) and pyre Sulfonate, Sodium Stibogluconate, Sodium Sulfate, Sodum throids, and carbamates (which include but are not limited to thiosulfate, Somatotropin, Sotalol, spectinomycin, spirono benomyl, carbanolate, carbaryl, carbofuran, meththiocarb, lactone, stanozolol, Streptokinase, Streptozocin, Succimer, metolcarb, promacyl, propoXur, aldicarb, butocarboxim, Succinylcholine chloride, Sucralfate, Sufentanil citrate, Sul oxamyl, thiocarboxime and thiofanoX). fachlorpyridazine Sodium, Sulfadiazine/trimethroprim, Sul 0.132. In some embodiments, the compositions of the famethoxazole/trimethoprim, Sulfadimentoxine, Sul invention may include one or more antinematodal agents fadimethoxineformetoprim, Sulfasalazine, taurine, including, but not limited to, active agents in the benzimida tepoxaline, terbinafline, terbutaline sulfate, testosterone, tet Zoles, imidazothiazoles, tetrahydropyrimidines, organophos US 2013/014395.6 A1 Jun. 6, 2013

phates class of compounds. In some embodiments, benzimi 1H-isoindole-1,3(2H)dione (MGK-264), dipropyl-2,5- dazoles including, but not limited to, thiabendazole, pyridinedicarboxylate (MGK-326) and 2-(octylthio)ethanol cambendazole, parbendazole, oxibendazole, mebendazole, (MGK-874). flubendazole, fenbendazole, Oxfendazole, albendazole, 0.138. An antiparasitic agent that can be combined with the cyclobendazole, febantel, thiophanate and its o.o-dimethyl compound of the invention to form a composition can be a analog may be included in the compositions. biologically active peptide or protein including, but not lim ited to, depsipeptides, which act at the neuromuscular junc 0133. In other embodiments, the compositions may tion by stimulating presynaptic receptors belonging to the include an imidazothiazole compounds including, but not secretin receptor family resulting in the paralysis and death of limited to, tetramisole, levamisole and butamisole. In still other embodiments, the compositions of the invention may parasites. In one embodiment of the depsipeptide, the dep include tetrahydropyrimidine active agents including, but not sipeptide is emodepside (see Willson et al., Parasitology, limited to, pyrantel, oxantel, and morantel. Suitable organo January 2003, 126(Pt 1):79-86). phosphate active agents include, but are not limited to, cou 0.139. An insecticidal agent that can be combined with the maphos, trichlorfon, haloxon, naftalofos and dichlorvos, hep compound of the invention to form a composition can be a tenophos, mevinphos, monocrotophos, TEPP, and spinosyn (e.g. spinosad) or a Substituted pyridylmethyl tetrachlorvinphos. derivative compound such as imidacloprid. Agents of this class are described above, and for example, in U.S. Pat. No. 0134. In other embodiments, the compositions may 4,742,060 or in EP 0892060, both of which are incorporated include the antinematodal compounds phenothiazine, pipera herein by reference. It would be well within the skill level of Zine as the neutral compound and in various salt forms, dieth the practitioner to decide which individual compound can be ylcarbamazine, phenols such as disophenol, arsenicals such used in the inventive formulation to treat a particular infection as arsenamide, ethanolamines Such as bephenium, thenium of an insect. closylate, and methyridine; cyanine dyes including pyrv 0140. In certain embodiments, an insecticidal agent that inium chloride, pyrvinium pamoate and dithiazanine iodide; can be combined with the compositions of the invention is a isothiocyanates including bitoscanate, Suramin Sodium, semicarbazone, such as metaflumizone. phthalofyne, and various natural products including, but not 0.141. In another embodiment, the compositions of the limited to, hygromycin B, C-santonin and kainic acid. invention may advantageously include one or more com 0135) In other embodiments, the compositions of the pounds of the isoxazoline class of compounds. These active invention may include antitrematodal agents. Suitable anti agents are described in WO 2007/079162, WO 2007/075459 trematodal agents include, but are not limited to, the miracils and US 2009/0133319, WO 2007/070606 and US 2009/ Such as miracil D and mirasan; praziquantel, clonazepam and 0.143410, WO 2009/003075, WO 2009/002809, WO 2009/ its 3-methyl derivative, oltipraZ, lucanthone, hycanthone, 024541, WO 2005/085216 and US 2007/0066617 and WO oxamniquine, amoscanate, niridazole, nitroxynil, various 2008/122375, all of which are incorporated herein by refer bisphenol compounds known in the art including hexachlo ence in their entirety. rophene, bithionol, bithionol sulfoxide and menichlopholan; 0142. In another embodiment of the invention, nod various Salicylanilide compounds including tribromsalan, ulisporic acid and its derivatives (a class of known acaricidal, oxyclozanide, clioxanide, rafoxanide, brotianide, bromox anthelmintic, anti-parasitic and insecticidal agents) may be anide and closantel; triclabendazole, diamfenetide, clorSulon, added to the compositions of the invention. These compounds hetolin and emetine. are used to treat or prevent infections in humans and animals and are described, for example, in U.S. Pat. Nos. 5,399.582, 0.136 Anticestodal compounds may also be advanta 5,962.499, 6,221,894 and 6,399,786, all of which are hereby geously used in the compositions of the invention including, incorporated by reference in their entirety. The compositions but not limited to, arecoline in various salt forms, bunami may include one or more of the known nodulisporic acid dine, niclosamide, nitroscanate, paromomycin and paromo derivatives in the art, including all stereoisomers, such as mycin II. those described in the literature cited above. 0.137 In yet other embodiments, the compositions of the 0143. In another embodiment, anthelmintic compounds of invention may include other active agents that are effective the amino acetonitrile class (AAD) of compounds Such as against arthropod parasites. Suitable active agents include, monepantel (ZOLVIX) and the like may be added to the but are not limited to, bromocyclen, chlordane, DDT. compositions of the invention. These compounds are endosulfan, lindane, methoxychlor, toxaphene, bromophos, described, for example, in WO 2004/024704; Sager et al., bromophos-ethyl, carbophenothion, chlorfenvinphos, chlo Veterinary Parasitology, 2009, 159, 49-54; Kaminsky et al., rpyrifos, crotoxyphos, cythioate, diazinon, dichlorenthion Nature vol. 452, 13 Mar. 2008, 176-181. The compositions of diemthoate, dioxathion, ethion, famphur, fenitrothion, the invention may also include aryloazol-2-yl cyanoethy fenthion, fospirate, iodofenphos, malathion, naled, phosa lamino compounds such as those described in US 2008/ lone, phosmet, phoxim, propetamphos, ronnel, Stirofos, 0312272 to Soll et al., which is incorporated herein in its allethrin, cyhalothrin, cypermethrin, deltamethrin, fenvaler entirety, and thioamide derivatives of these compounds, as ate, flucythrinate, permethrin, phenothrin, pyrethrins, res described in U.S. patent application Ser. No. 12/582.486, methrin, benzyl benzoate, carbon disulfide, crotamiton, filed Oct. 20, 2009, which is incorporated herein by reference. diflubenZuron, diphenylamine, disulfuram, isobornylthiocy 0144. The compositions of the invention may also be com anato acetate, methroprene, monosulfuram, pirenonylbutox bined with paraherquamide compounds and derivatives of ide, rotenone, triphenyltin acetate, triphenyltin hydroxide, these compounds, including derquantel (see Ostlind et al., deet, dimethyl phthalate, and the compounds 1.5a,6,9.9a,9b Research in Veterinary Science, 1990, 48, 260-61; and hexahydro-4-a(4H)-dibenzofurancarboxaldehyde (MGK Ostlind et al., Medical and Veterinary Entomology, 1997, 11, 11), 2-(2-ethylhexyl)-3 a.4,7,7a-tetrahydro-4,7-methano 407-408). The paraherquamide family of compounds are US 2013/014395.6 A1 Jun. 6, 2013 known class of compounds that include a spirodioxepino (10) from the order of Anoplura (Phthiraptera), for example, indole core with activity against certain parasites (see Tet. Damalinia spp., Haematopinus spp., Linognathus spp., Lett. 1981, 22, 135, J. Antibiotics 1990, 43, 1380, and J. Pediculus spp., Trichodectes spp.; Antibiotics 1991, 44, 492). In addition, the structurally related (11) from the class of Arachnida, for example, Acarus Siro, marcfortine family of compounds, such as marcfortines A-C, Aceria Sheldoni, Aculops spp., Aculus spp., Amblyomma spp., are also known and may be combined with the formulations Argas spp., Boophilus spp., Brevipalpus spp., Bryobia pra of the invention (see J. Chem. Soc.—Chem. Comm. 1980, 601 etiosa, Chorioptes spp., Dermanyssus gallinae, Eotetrany and Tet. Lett. 1981, 22, 1977). Further references to the para chus spp., Epitrimerus pyri, Eutetranychus spp., Eriophyes herquamide derivatives can be found, for example, in WO spp., Hemitarisonemus spp., Hyalomma spp., Ixodes spp., 91/09961, WO 92/22555, WO 97/03988, WO 01/076370, Latrodectus mactans, Metatetranychus spp., Oligonychus WO 09/004,432, U.S. Pat. No. 5,703,078 and U.S. Pat. No. spp., Ornithodoros spp., Panonychus spp., Phylocoptruta 5,750,695, all of which are hereby incorporated by reference oleivora, Polyp hagotarisonemus latus, Psoroptes spp., Rhi in their entirety. picephalus spp., Rhizoglyphus spp., Sarcoptes spp., Scorpio 0145. In a further aspect, the invention relates to a method maurus, Steneotarisonemus spp., Tarsonemus spp., Tetrany of treating livestock to prevent or decrease the level of infec chus spp., Vasates lycopersici; tion by endo- and/or ecto-parasites, which may comprise (12) from the class of Bivalva, for example, Dreissena spp.; administering to the livestock an anti-parasitic formulation as (13) from the order of Coleoptera, for example, Acan described herein. thoscelides Obtectus, Adoretus spp., Agelastica alni, Agriotes 0146 When an anthelmintic agent is added to the compo spp., Amphimallon solstitialis, Anobium punctatum, Anoplo sition of the invention, the composition can also be used to phora spp., Anthonomus spp., Anthrenus spp., Apogonia spp., treat against endoparasites such as those helminths selected Atomaria spp., Attagenus spp., Bruchidius Obtectus, Bruchus from the group consisting of Anaplocephala, Ancylostoma, spp., Ceutorhynchus spp., Cleonus mendicus, Conoderus Anecator; Ascaris, Capillaria, Cooperia, Dipylidium, Dirofi spp., Cosmopolites spp., Costelytra zealandica, Curculio laria, Echinococcus, Enterobius, Fasciola, Haemonchus, spp., Cryptorhynchus lapathi, Dermestes spp., Diabrotica Oesophagostumum, Ostertagia, Toxocara, Strongyloides, spp., Epilachna spp., Faustinus cubae, Gibbium psylloides, Toxascaris, Trichinella, Trichuris, and Tricho strongylus. Heteronychus arator, Hylamorpha elegans, Hylotrupes baju In another embodiment of the invention, the compounds and lus, Hypera postica, Hypothenemus spp., Lachnosterna Con compositions of the invention are Suitable for controlling sanguinea, Leptinotarsa decemlineata, Lissorhoptrus Oryzo pests such as insects selected from the group consisting of philus, Lixus spp., Lyctus spp., Melligethes aeneus, Blattella germanica, Heliothis virescens, Leptinotarsa Melolontha melolontha, Migdolus spp., Monochamus spp., decemlineata, Tetramorium caespitum and combinations Naupactus xanthographus, Niptus hololeucus, Oryctes rhi thereof. noceros, Oryzaephilus Surinamensis, Otiorrhynchus sulca 0147 The phytoparasitic nematodes include, for example, tus, Oxycetonia jucunda, Phaedon cochleariae, Phyllophaga Anguina spp., Aphelenchoides spp., Belonolaimus spp., Bur spp., Popillia japonica, Premnotrypes spp., Psylliodes Saphelenchus spp., Dity lenchus dipsaci, Globodera spp., chrysocephala, Ptinus spp., Rhizobius ventralis, Rhizopertha Helicotylenchus spp., Heterodera spp., Longidorus spp., dominica, Sitophilus spp., Sphenophorus spp., Sternechus Meloidogyne spp., Pratylenchus spp., Radopholus similis, spp., Symphyletes spp., Tenebrio molitor; Tribolium spp., Tro Rotylenchus spp., Trichodorus spp., Tilenchorhynchus spp., goderma spp., Tichius spp., Xylotrechus spp., Zabrus spp.; Tvlenchulus spp., Tilenchulus semipenetrans, Xiphinema (14) from the order of Diptera, for example, Aedes spp., spp. Anopheles spp., Bibio hortulanus, Caliphora erythro 0148. In addition, with or without the other pesticidal cephala, Ceratitis capitata, Chrysomyia spp., Cochliomyia agents added to the composition, the invention can also be spp., Cordylobia anthropophaga, Culex spp., Cuterebra spp., used to treat other pests which include but are not limited to Dacus oleae, Dermatobia hominis, Drosophila spp., Fannia pests: spp., Gastrophilus spp., Hyllemyia spp., Hyppobosca spp., (1) from the order of Isopoda, for example Oniscus asellus, Hypoderma spp., Liriomyza spp., Lucilia spp., Musca spp., Armadillidium vulgare and Porcellio scaber, Nezara spp., Oestrus spp., Oscinella frit, Pegomyia hyos (2) from the order of Diplopoda, for example Blaniulus gut cyani, Phorbia spp., Stomoxys spp., Tabanus spp., Tannia tulatus, spp., Tipula paludosa, Wohlfahrtia spp.; (3) from the order of Chilopoda, for example Geophilus car (15) from the class of Gastropoda, for example, Anion spp., pophagus and Scutigera spp.; Biomphalaria spp., Bulinus spp., Denocenas spp., Galba (4) from the order of Symphyla, for example Scutigerella spp., Lynnaea spp., Oncomelania spp., Succinea spp.; immaculata, (16) from the class of helminths, for example, Ancylostoma (5) from the order of Thysanura, for example Lepisma sac duodenale, Ancylostoma ceylanicum, Ancylostoma brazilien charina, sis, Ancylostoma spp., Ascaris lubnicoides, Ascaris spp., Bru (6) from the order of Collembola, for example Onychiurus gia malayi, Brugia timoni, Bunostomum spp., Chabertia spp., arnatus, Clononchis spp., Cooperia spp., Dicrocoelium spp., Dictyo (7) from the order of Blattaria, for example Blatta Orientalis, caulus filaria, Diphyllobothrium latum, Dracunculus medin Periplaneta americana, Leucophaea maderae and Blattella ensis, Echinococcus granulosus, Echinococcus multilocu germanica, laris, Enterobius vermicularis, Faciola spp., Haemonchus (8) from the order of Hymenoptera, for example Diprion spp., spp., Heterakis spp., Hymenolepis nana, Hvostrongulus spp., Hoplocampa spp., Lasius spp., Monomorium pharaonis and Loa Loa, Nematodirus spp., Oesophagostomum spp., Vespa spp.; Opisthorchis spp., Onchocerca volvulus, Ostertagia spp., (9) from the order of Siphonaptera, for example Xenopsylla Paragonimus spp., Schistosomen spp., Strongyloides fielle cheopis and Ceratophyllus spp.; bonni, Strongyloides Stercoralis, Stronyloides spp., Taenia US 2013/014395.6 A1 Jun. 6, 2013 11 saginata, Taenia Solium, Trichinella spinalis, Trichinella antennata, Loxagrotis albicosta, Lymantria spp., Malaco nativa, Trichinella britovi, Trichinella nelsoni, Trichinella Soma neustria, Mamestra brassicae, Mods repanda, pseudopsinalis, Tinicho strongulus spp., Trichuris trichuria, Mythinna separata, Oria spp., Oulema Oryzae, Panolis flam Wuchereria bancrofti, mea, Pectinophora gossypiella, Phyllocnistis citrella, Pieris (17) from the order of Heteroptera, for example, Anasa tristis, spp., Plutella xylostella, Prodenia spp., Pseudaletia spp., Antestiopsis spp., Blissus spp., Caloconis spp., Campylomma Pseudoplusia includens, Pyrausta nubilalis, Spodoptera livida, Cavelenius spp., Cimex spp., Creontiades dilutus, spp., Thermesia gemmatalis, Tinea pellionella, Tineola bis Dasynus pipenis, Dichelops funcatus, Diconocoris hewetti, selliella, Tortrix viridana, Trichoplusia spp.; Dysdercus spp., Euschistus spp., Eurygaster spp., Heliopeltis (21) from the order of Orthoptera, for example, Acheta spp., Honcias nobilellus, Leptoconisa spp., Leptoglossus domesticus, Blatta Orientalis, Blattella germanica, Gryllo phyllopus, Lygus spp., Macropes excavatus, Mimidae, talpa spp., Leucophaea maderae, Locusta spp., Melanoplus Nezara spp., Oebalus spp., Pentomidae, Piesma quadrata, spp., Periplaneta americana, Schistocerca gregaria, Piezodorus spp., Psalus seniatus, Pseudacy.sta persea, (22) from the order of Thysanoptera, for example, Baliothrips Rhodnius spp., Sahlbergella singulanis, Scotinophora spp., biformis, Enneothrips flavens, Frankliniella spp., Heliothrips Stephanitis nashi, Tibraca spp., Triatoma spp.; spp., Hercinothrips femoralis, Kakothrips spp., Rhipiphoro (18) from the order of Homoptera, for example, Acynthosi thrips cruentatus, Scirtothrips spp., Taeniothrips cardamoni, phon spp., Aeneolamia spp., Agonoscena spp., Aleunodes Thrips spp.; spp., Aleunolobus banodensis, Aleunothnixus spp., Amnasca (23) from the class of Protozoa, for example, Eimeria spp. spp., Anunaphis candui, Aonidiella spp., Aphanostigma pini, 0149. In each aspect of the invention, the compounds and Aphis spp., Ambonidia apicalis, Aspidiella spp., Aspidiotus compositions of the invention can be applied against a single spp., Atanus spp., Aulaconthum Solani, Bemisia spp., Brachy pest or combinations thereof. caudus helichrysii, Brachycolus spp., Brevicoryne brassicae, 0150. The above description of the invention is intended to Calligypona manginata, Carneocephalafiulgida, Cenatova be illustrative and not limiting. Various changes or modifica cuna lanigena, Cencopidae, Cenoplastes spp., Chaetosiphon tions in the embodiments described may occur to those fragaefolii, Chionaspis tegalensis, Chlomita Onuki, Chroma skilled in the art. These can be made without departing from phis juglandicola, Chrysomphalus ficus, Cicadulina mbila, the scope or spirit of the invention. Coccomytilus halli, Coccus spp., Cryptomyzus nibis, Dalbu 0151. The invention is further described, for example, in lus spp., Dialeunodes spp., Diaphonina spp., Diaspis spp., the following non-limiting examples. Better understanding of Dorsalis spp., Drosicha spp., Dysaphis spp., Dysmicoccus the present invention and of its many advantages will be had spp., Empoasca spp., Eriosoma spp., Erythroneura spp., Eus from the following non-limiting examples, given by way of celis bilobatus, Geococcus coffeae, Homalodisca coagulata, illustration. It will be apparent to those skilled in the art that Hyalopterus arundinis, Icerya spp., Idiocerus spp., Idiosco these examples are non-limiting, and that similar methods to pus spp., Laodelphax striatellus, Lecanium spp., Lepi achieve the following transformations are possible. dosaphes spp., Lipaphis erysimi, Macrosiphum spp., Maha 0152 The following examples describe the preparation of marva fimbriolata, Melanaphis sacchari, Metcalfiella spp., Metopolophium dirhodium, Monellia Costalis, Monelliopsis various pecanis, Myzus spp., Nasonovia ribismigri, Nephotettix spp., Nilaparvata lugens, Oncometopia spp., Orthezia praelonga, Example 1 Parabemisia myricae, Paratrioza spp., Parlatoria spp., Pem phigus spp., Peregrinus maidis, Phenacoccus spp., Phlo Production and Analysis of Moxidectin Crystalline eomyzus passerinii, Phorodon humuli, Phylloxera spp., Pin Forms naspis aspidistrae, Planococcus spp., Protopulvinaria 0153 Methods. pyriformis, Pseudaulacaspis pentagona, Pseudococcus spp., 0154) Differential Scanning Calorimetry (DSC). Psylla spp., Pteromalus spp., Pyrilla spp., Ouadraspidiotus 0155 The samples were subjected to three modes of test spp., Quesada gigas, Rastrococcus spp., Rhopalosiphum ing with TA Instruments Q100 to determine the thermal spp., Saissetia spp., Scaphoides titanus, Schizaphis grami possibilities. num, Selenaspidus articulatus, Sogata spp., Sogatella fur cifera, Sogatodes spp., Stictocephala festina, Tenalaphara 0156 1. The Conventional DSC method was used involv malayensis, Tinocallis caryaefoliae, Tomaspis spp., Tox ing the following steps: optera spp., Trialeurodes vaporariorum, Trioza spp., Tiphlo (O157 a) Equilibrate at 20° C. for 3 minutes. cyba spp., Unaspis spp., Viteus vitifolii; 0158 b) Ramp 10° C./minute to 250° C. HEAT (19) from the order of Isoptera, for example, Reticulitermes 0159 2. The Modulated DSC with the following sequence spp., Odontotermes spp.; of steps: (20) from the order of Lepidoptera, for example, Acronicta (0160 a) Equilibrate at 200° C. major; Aedia leucomelas, Agrotis spp., Alabama argillacea, (0161 b) Modulate:1° C. every 60 seconds. Anticarsia spp., Barathra brassicae, Bucculatrix thurberi 0162 c) Isothermal for 5 minutes. ella, Bupalus piniarius, Cacoeciapodana, Capua reticulana, (0163 d) Ramp 50° C. per minute to 200° C. Carpocapsa pomonella, Chematobia brumata, Chilo spp., Choristoneura filmiferana, Clysia ambiguella, Cnaphalo 0164 3. The Heat-Cool-Heat method at a higher tempera cerus spp., Earias insulana, Ephestia kuehniella, Euproctis ture range: chrysorrhoea, Euxoa spp., Feltia spp., Galleria mellonella, (0165) a) Equilibrate at 20° C. for 3 minutes. Helicoverpa spp., Heliothis spp., Hofmannophila pseu (0166 b) Ramp 10° C./minute to 200° C. HEAT dospretella, Homona magnanima, Hyponomeuta padella, (0167 c) Ramp 10° C./minute to 20° C. COOL Laphygma spp., Lithocolletis blancardella, Lithophane (0168 d) Ramp 10° C./minute to 250° C. HEAT US 2013/014395.6 A1 Jun. 6, 2013

(0169. Thermal Gravity Analysis (TGA). In the first experiment, the moxidectin was cooled down from (0170 TGA was performed on PerkinElmer Pyris 1 TGA 193°C., which was just above the crystallization temperature, instrument. Samples were equilibrated at 22°C. for 1 minute, as shown in FIG. 4. The reheating experiment showed that the then heat was applied at ramp of 10°C/minute to 300° C. sample still contained a certain amount of amorphous mate (0171 X-Ray Powder Diffraction (XRPD). rial due to the presence of the glass transition at 105°C. In 0172 Patterns were obtained at room temperature on Shi contrast, the second heat cycle exhibited a melting endotherm madzu's XRD-6000. The isothermal measurement condi without evidence of crystallization. This indicates that the tions were as follows: moxidectin crystallization was complete during the initial (0173 Target: Cu heat cycle. After cooling the sample from 198°C. to a tem (0174 Voltage: 40 kV perature below the previously observed crystallization tem (0175. Current: 40 mA perature, (FIG. 5), reheating showed no evidence of the pre (0176) Divergence Slit: 1.0 mm viously observed glass transition, Suggesting that all of the 0177 Anti-scatter Slit: 1.0 mm moxidectin crystallized during the first heat cycle. This is (0178 Receiving Slit: 0.15 mm further supported by the observation of the melting point even 0179 Monochromator: None though no crystallization transition was observed during the 0180. Detector Slit: 0.15 mm second heat cycle. After cooling the sample from 220° C. 0181 Scan range: 2 to 40 deg (FIG. 6), which was higher than the melting point but below 0182 Scanning Speed: 1 deg/minute the decomposition temperature, the second heat cycle showed 0183 Step Size: 0.02 deg only the glass transition, indicating that the sample became 0184 Preset Time: 1.20 sec amorphous upon cooling of the molten material. 0185. The XRPD diffractograms of the samples were 0197) The modulated DSC is shown in FIG. 7. This result compared with regard to peak position and relative intensity, is consistent with those obtained from conventional DSC. A peak shifting, and the presence or lack of peaks in certain glass transition appeared in the reversible heat flow experi angular regions. ment, while the relaxation enthalpy, crystallization and 0186 Optical Microscopy. decomposition were observed under irreversible heat flow 0187. The optical photomicrographs were obtained at conditions. Melting occurred in both the reversible and irre room temperature on Axioskop 40 polarized light microscope versible heat flow modes. from Zeiss. Under reflected light and grazing illumination, (0198 Thermally Transformed Moxidectin. the images at 5x magnification were captured through a (0199. Approximately 1 g of moxidectin (lot S090601) was charge-coupled device (CCD) camera, and were processed placed in a glass vial, which was then placed in a hot oil bath and enhanced using Axiovision Version 4.3 software. at ~190° C. and held at that temperature for approximately 5 0188 Attenuated Total Reflectance Infrared (ATR-IR) minutes. Upon cooling the material had yellowed slightly. Spectroscopy. The yellowish Solid was collected and ground in a mortar and 0189 A diamond ATR (Smart Orbit) accessory, and a pestle. To evaluate the purity of the moxidectin which had Nicolet 6700 FTIR from ThermoEisher were used with the been subjected to these conditions, HPLC and LC-MS were following instrument conditions: 1) Scan range: 4000 to 650 performed. The powder was analyzed by powder X-ray dif cm'; 2)32 scans; and 3) 4 cm resolution. fraction (PXRD) spectroscopy. The PXRD pattern shows sig 0190. Raman Spectroscopy. nificant diffraction peaks indicative of the presence of a siZ (0191 DXR Raman Microscope from ThermoFisher was able amount of crystalline material although a certain amount used with the following instrument conditions: 1) Exposure ofamorphous material still remained as evidenced by the halo time=20s; 2) 32 scans; 3) 24 sample scans; and 4) 32 back envelope in the diffraction pattern. This indicates that amor ground scans. phous moxidectin crystallizes upon heating to 190° C. (FIG. 0.192 Moisture Sorption Gravimetric Analysis (SGA). 8). (0193 Utilizing a dynamic SGA100 from VTI, adsorption 0200. The IR and Raman spectra of amorphousand ther and desorption profiles were obtained with the following mally transformed crystalline moxidectin are shown in FIG.9 conditions: 1) Isothermal (a 25°C.; 2) Maximum Equilibra and FIG. 10. Compared with amorphous moxidectin, crystal tion Time of 10 minutes; 3) 0.0010 wt % in 5 minutes; and 4) line moxidectin shows two sharp peaks, 3471 cm and 3541 % RH (Relative Humidity) Steps of 5 to 95, and 95 to 5(a).5% cm superimposed on the broad peakaround 3500 cm. The increments. carbonyl stretching vibration of crystalline moxidectin shows 0194 Thermal Analysis of Commercial Moxidectin (Lot slight red shift to 1707 cm from 1712 cm. This demon #S090601) strates that these peaks in the IR can be used to distinguish this (0195 The conventional DSC of lot 5090601 is depicted in crystalline form from amorphous moxidectin. FIG. 2A. It shows an endothermal event at 114°C., which is 0201 A hot stage microscopic image was taken (FIG. 11) attributed to the glass transition of moxidectin. Starting from of this thermal transition. The bulk, amorphous moxidectin 174° C., it presents a broad exotherm centered at 186°C., demonstrated a wetting phenomenon around 120° C. The which is presumably the crystallization of rubbery moxidec wetting increased significantly with increasing temperature tin. Immediately following the crystallization, a sharp endot and the sample appeared to flow, indicating that the sample herm occurs at 206°C., which demonstrates the melting point had undergone a glass transition. This parallels the DSC of crystalline moxidectin Form A. The moxidectin starts to observation. Between 120 and 170° C., the sample main decompose above 230°C. The PXRD confirms that the origi tained this rubbery state. At about 185°C., white spots began nal moxidectin (lot S090601) is amorphous as shown in FIG. appearing and a large patch of “prismatic crystals' appeared 3. at 190° C. More crystals developed with increasing tempera 0196. To better understand its thermal behavior, several ture to 205°C. Above 210°C., the crystals began to melt with heating-cooling-heating cycle experiments were performed. completion at 218°C. The compound decomposed around US 2013/014395.6 A1 Jun. 6, 2013

230° C. The hot-stage microscopic experiment verified the space group with the cell parametera=11.2731 (15) A, b=8. DSC result, confirming the transformation of moxidectin 9286(12) A, c=21.955(3) A, R=93.623(2), V=2205.4(5) A, from amorphous state through glass transition to a rubbery Z=2. state followed by crystallization and Subsequent melting then 0213. There are one moxidectin and two ethanol mol decomposition. ecules per asymmetric unit as depicted in FIG. 22. This is 0202 Preparation and Characterization of Moxidectin/ consistent with the TGA result. One ethanol is hydrogen MeOH bonded with one hydroxyl group of moxidectinas a donorand 0203 To 0.5 ml methanol at 50-60° C. amorphous mox the other ethanol is hydrogen bonded to another hydroxyl idectin (lotifS090601) was added gradually until the solution group of moxidectin as an acceptor. Moxidectin molecules became Saturated. The resulting mixture was cooled to room are connected together by hydrogen bonds, forming a channel temperature and rod-like crystals formed after a short period along the crystallographic a direction, in which ethanol mol of time. The solid was filtered and the crystal image is pre ecules are accommodated (FIG. 23). sented in FIG. 12. The crystals were birefringent, indicative 0214 Preparation and Characterization of Moxidectin. of crystallinity. Moxidectin/MeOH crystals were dried in air IPA. for 1 h. The powder X-ray diffraction confirmed its high 0215. To 1 ml isopropanol solution, amorphous moxidec degree of crystallinity (FIG. 13). tin (lotii S090601) was added gradually to saturation at 50-60° C. The resulting solution was cooled and held at room tem 0204 Thermal analysis of air-dried Moxdectin. MeOH perature resulting in rapid formation of large prismatic crys crystals demonstrated a weight loss of 0.98% between tals. The crystal image was taken and depicted in FIG. 24. 50-150° C. (FIG. 14). The compound decomposes above Moxidectin IPA crystals were isolated and air-dried for 2 h. 2500 C. Powder X-ray diffraction shows that these crystals are highly 0205 DSC did not show the corresponding solvent loss crystalline (FIG. 25). When moxidectin (lotiiO70201, which due to its low content. It exhibits a small exotherm around does not contain BHT) was used for crystallization, the crys 150° C., then melts at 214° C. (FIG. 15). The small peak at tals were also formed as shown in FIG. 26. The thermal 150° C. results from either solvent evaporation or phase tran analysis of air-dried Moxidectin IPA crystals displayed a sition. The melting point is very close to that obtained from single weight loss of 14.87% from 25-200° C. (FIG. 27). This amorphous moxidectin, Suggesting that they might be the weight loss approximately corresponds to two moles of IPA same form. per moxidectin. The theoretical calculation based on moX 0206 Preparation and characterization of Moxidectin.E- idectin:IPA=1:2 gives 15.78% IPA weight content which is in tOH. reasonably good agreement with the experimental data. The 0207 To 1 ml ethanol, amorphous moxidectin compound decomposes above 250° C. (lotiS090601) was added gradually at 50-60° C. until the 0216. DSC of this material demonstrated a sharp endot Solution was saturated. The resulting mixture was left at room herm with a shoulder at 90° C. (FIG. 28), which probably temperature and quickly formed large crystals having corresponds to the solvent loss of IPA. The small peak at 130° approximate dimensions of about 2 mmx2 mmx0.5 mm. One C. results from either solvent evaporation or phase transition, representative crystal was crushed and the crystal image was and needs to be further investigated. taken, which is depicted in FIG. 16. 0217. The Moxdectin IPA crystals were dried under 0208 Moxidectin EtOH crystals were separated and air vacuum at 100° C. for 30 min. DSC shows the vacuum-dried dried for 2 h. The crystals were ground with a mortar and moxidectin becomes amorphous (FIG. 29). pestle and analyzed by powder X-ray diffraction and thermal 0218. Preparation and Characterization of Moxidectin analysis. PXRD shows a strong diffraction pattern (FIG. 17), n-Butanol. which is different from that of moxidectin MeOH, indicating 0219. To 0.5 ml of n-butanol, amorphous moxidectin that they have different crystal forms. (lotifS090601) was added gradually to saturation (maintain 0209. The thermal gravimetric analysis of air-dried Mox ing temperature between 50-60° C.). The mixture was then idectin EtOH demonstrated a weight loss of 11.87% upon transferred to -10°C. over night, during which time crystals heating from 25 to 200° C. (FIG. 18). This weight loss had formed (FIG. 30). Moxidectin/n-butanol crystals were roughly corresponds to two mole of ethanol per mole of separated and dried in air for 2 h. Powder X-ray diffraction moxidectin. The theoretical calculation based on moxidectin: shows that these crystals are highly crystalline (FIG. 31). ethanol=1:2 gives 12.57% ethanol weight content which is 0220. Thermal analysis of air-dried Moxidectin n-butanol consistent with the experimental value. The compound displays a weight loss of 14.94% upon heating from 25 to decomposes above 250° C. 150° C. (FIG. 32). This weight loss corresponds to 1.5 moles of n-butanol per mole of moxidectin. The theoretical calcu 0210. The DSC of this material exhibits a sharp endotherm lation based on moxidectin:n-butanol=1:1.5 gives 14.78% with a shoulder at 90° C., which probably corresponds to loss n-butanol weight content. The compound decomposes above of ethanol as shown in FIG. 19. 2500 C. 0211. The Moxidectin EtOH crystals were dried under 0221) DSC exhibits a sharp endothermat 65° C. (FIG.33), vacuum at 100° C. for 4 h. DSC shows the vacuum-dried which likely corresponds to the loss of n-butanol. The desol moxidectin became amorphous (FIG. 20). This is further vated moxidectin melts at 215°C., which corresponds to the confirmed by powder X-ray diffraction. Only a few small melting point of Polymorph A. The desolvation temperature scattered peaks appear on the PXRD (FIG. 21), due likely to is relatively low compared with moxidectin EtOH and mox incomplete collapse of the structure upon removal of the idectin. IPA, suggesting that n-butanol is loosely bound with solvent. the moxidectin molecule. 0212. The single crystal structure of crystalline Moxidec 0222 To confirm the process of desolvation of moxidec tin EtOH was determined demonstrating a monoclinic P2 tinn-butanol, the crystals were dried under vacuum at 60° C. US 2013/014395.6 A1 Jun. 6, 2013

for 2 h. The DSC and PXRD show the vacuum-dried mox C., amorphous moxidectin crystallizes, and this transition has idectin became amorphous after drying (FIGS. 34 and 35). the effect of altering the release profile of any polymeric Less rigorous drying conditions did not successfully desol implants produced. vate the material (FIG. 36). 0230 Polymeric Implants. 0223 Preparation and Characterization of Moxidectin 0231. A solution of moxidectin (40% w/w), BHT (1.4%) MCH. and poly d lactide-glycolide (75:25 L:G: 0.4 iv) was prepared 0224. To 1 ml methylcyclohexane (MCH) solution, about in methylene chloride and spray dried on a Buchi spray drier. 500 mg amorphous moxidectin (lotifS090601) was added The spray dried powder was placed in the Tenius Olsen plas while heating to 50-60° C. and the mixture was concentrated tometer and extruded at 118°C. The resulting -0.8 mm diam by evaporation. After cooling to room temperature, hexane eter polymer Strand was cut into Small pellets -2 mm in was added and solid precipitate formed. The solid was length. Five pellets were placed in a Scintillation vial contain washed with hexane and dried at room temperature for a short ing 10 mL 2% SDS in PBS, pH 7. Triplicate vials were period of time (image, FIG. 37). Powder X-ray diffraction prepared and placed in a 37° C. shaking (120 rpm) water bath. demonstrated its crystallinity (FIG.38). The Solution was removed at each sampling point, replaced 0225. Thermal analysis of air-dried Moxdectin.MCH with fresh 2% SDS in PBS and assay by HPLC. The results crystal demonstrated a weight loss of 1.68% upon heating are shown in FIG. 44. The in vitro release profile is provided from 50 to 150° C. (FIG. 39). The compound decomposes in FIG. 44. Additionally, samples were assayed by DSC (FIG. above 250° C. DSC demonstrated an apparent melting point 43). Moxidectin was amorphous in the pellet samples. at 211° C. (FIG. 40). This melting temperature is in agree 0232. In an alternate batch, a solution of moxidectin (40% ment with that of the thermally transformed solid and Mox w/w), BHT (1.4%), and poly d lactide-glycolide (75:25 L:G: idectin MeCH, implying that they are the same crystalline 0.4 iv) was prepared in methylene chloride and spray dried on form. Further, the PXRD patterns of the moxidectin crystals a Buchi spray drier. The spray dried powder was placed in 3/8" obtained from methanol and MCH are identical (FIG. 13 for single screw extruder (0.75 mm short land die, elongational MeOH vs. FIG. 41 for MCH) further confirming the similar mixing screw, K-Tron micro feeder set to 24 g/hr) and ity of the crystal forms from the two solvent systems extruded at 130°C. The resulting -0.8 mm diameter polymer 0226 Conclusions. Strand was cut into Small pellets ~2 mm in length. Five pellets 0227. A series of crystalline moxidectin forms were were placed in a scintillation vial containing 10 mL 2% SDS obtained from alcohol solvents including methanol, ethanol, in PBS, pH 7. Triplicate vials were prepared and placed in a IPA and butanol etc. Those prepared from methanol and 37° C. shaking (120 rpm) water bath. The solution was methylcyclohexane have essentially the same PXRD patterns removed at each sampling point, replaced with fresh 2% SDS as the thermally transformed one, indicating they have similar in PBS and assay by HPLC. The in vitro dissolution data are crystal form. Recrystallization of moxidectin from ethanol, shown in FIG. 45. IPA and n-butanol produce their respective solvates. The moxidectin EtOH and moxidectin. IPA solvates become Example 3 amorphous after loss of Solvents, while Surprisingly and unexpectedly, the moxidectin n-butanol remains crystalline Moxidectin Plasma Profile in Canines Injected with upon rapid removal of Solvent. Crystalline moxidectin is Polymeric Implants almost non-hygroscopic, while amorphous moxidectin is slightly hygroscopic. 0233. On Day 0, five canine animals were administered Subcutaneously one injection of 4 implants (containing 2000 Example 2 mcg amorphous moxidectin, 75:25 DLG (0.4 i.v.), prepared as above-loth 438-148), a separate implant needle containing Preparation of Slow-Release Polymeric Implants the appropriate number of implants was used for each treated Comprising Moxidectin, and In Vitro Release animal. Blood samples (approximately 5 to 7 mL) were col Profiles lected in individually labeled heparinized tubes. Plasma was recovered and stored frozen in aliquots, until required for 0228 Summary. assay. Canine study data results are shown in FIG. 46. Addi 0229. The crystal form properties of moxidectin API are tionally, implant samples were also assayed by DSC and IR depicted in FIGS. 2-8 and 10-12: including glass transition which determined that Moxidectin was amorphous in the temperature, crystallization and the crystal melt. Polymeric implant. implants containing either amorphous or crystalline mox 0234 Having thus described in detail the preferred idectin were prepared. For amorphous moxidectin implants, embodiments of the present invention, it is to be understood the process temperature was kept between ~120-170° C. that the above description of the invention is intended to be Inventors envision that any temperature above 120° C. (but illustrative and not limited to particular details set forth in the below moxidectin’s decomposition temperature) would be above description, as many apparent variations thereof are acceptable as the moxidectin would flow above its glass tran sition temperature and would be more easily extruded with possible. Various changes or modifications in the embodi increasing temperature (i.e. from 120 to 170° C.). The inven ment described may occur to those skilled in the art. These tors found Surprisingly and unexpectedly that moxidectin variations, changes and modifications can be made without crystallizes above 170° C. Thus, there is a narrow temperature departing from the scope or spirit of the invention. range that is optimal for preparation of the inventive implants, What is claimed is: and processing at a temperature higher than re-crystallization 1. Polymorphic A form of moxidectin having a melting temperature, though it runs counter to expectation, is not point of about 210°C. desirable for producing implants containing amorphous mox 2. Moxidectin.2EtOH solvate characterized by the follow idectin. When processed at temperatures between 180-210 ing parameters: US 2013/014395.6 A1 Jun. 6, 2013 15

a) monoclinic P2 space group with the 13. The implant of claim 6 wherein the animals are cats or b)a=11.2731(15) A: dogs or cattle. c) b=8.9286(12) A: 14. A method of producing the implant of claim 6 compris d) c=21.955(3) A: ing the steps of e) p=93.623(2): a) producing a solution of moxidectin and PLGA in a suitable solvent; f) V=2205.4(5) A: b) adding from 0-1% (w/w) antioxidant; c) removing the solvent using a suitable drying means; 3. Moxidectin. 1.5BuOH Solvate. d) Subjecting the dried material of step c to extrusion at a 4. Moxidectin.2IPA solvate. Suitable temperature to produce polymer Strands; 5. A process for making the moxidectin crystal form of e) cutting or otherwise reducing the size of the polymer claim 1 comprising the step of heating amorphous moxidectin strands, thereby producing the implant. under specific conditions of temperature and time, or rapidly 15. The method of claim 14 wherein the solvent is meth desolvating the moxidectin Solvate of claim 2, thereby mak ylene chloride and the drying means is a Buchi spray drier. ing the crystal form. 16. The method of claim 14 wherein the extrusion is per 6. Along-acting polymeric implant for non-human animals formed at a temperature Suitable for retaining the moxidectin comprising PLGA and amorphous moxidectin. in an amorphous state. 7. The implant of claim 6 wherein the PLGA has an L:G 17. The method of claim 16 wherein the extrusion is not ratio of about 50-75% to about 25-50% L:G. performed above 180° C. 8. The implant of claim wherein the L: G ratio is 75:25. 18. The method of claim 17 wherein the extrusion is per 9. The implant of claim 8 which is active against endopara formed at between about 110° C. and about 180° C. sites for a period of greater than 3 months. 19. The method of claim 18 wherein the extrusion is per 10. The implant of claim 9 which is active against formed at about 118° C. endoparasites for a period of greater than 4 months. 20. A composition for the treatment or prevention of a 11. The implant of claim 10 which is active against parasitic infection in an animal comprising the moxidectin endoparasites for a period of greater than 6 months. crystal form of claim 1, or a pharmaceutically acceptable salt 12. The implant of claim 6 wherein the endoparasites are thereof, and a pharmaceutically acceptable carrier. heartworms. k k k k k