ZA200609807B - Crystalline polymorphic forms of monosodium N-[8-(2-hydroxybenzoyl)amino]caprylate - Google Patents

Description

Crystalline Polymorphic Forms of Monosodium N-[8-(2- hydroxybenzoyl)amino]ca prylate [ 1] This application claims the bene=fit of U.S. Provisional Application

No. 60/569,476, filed May 6, 2004, and U.S. Provisional Application No. 60/619,48 18, filed October 15, 2004, both of which are hereby incorporated by reference.

Field of the Inwention

[2] The present invention relates to crystalline polymorphic forms of monosodium NI -[8-(2-hydroxybenzoyl)amino]caprylate, amorphous monosodium N-[8-(2- hydroxybenzoy1)aminojcaprylate, pharmaceutical compositions containing the sa me, methods of pre-paring the same, and methods for facillitating the delivery of active ag ents with the same.

Background of the Invention

C3) U.S. Patent No. 5.650,386 discloses N-[8-(2- hydroxybenzoy 1)amino]caprylic acid and salts thereof, and their use for facilitating the delivery of vari ous active agents.

Summary of thae Invention

[4] The present invention relates ®o polymorphic forms of monosod mum

N-[8-(2-hydroxybenzoyl)amino] caprylate (“SNAC™), including two hydrates, a methanol/water co-solvate, and an ethanol/water co—solvate, of SNAC. More specific -ally, the present invention provides six polymorphic forms of SNAC (hereafter referred to =as

Forms I-VI). The present invention also provides am amorphous form of SNAC.

[5] One embodiment of the invention is a pharmaceutical compositiaon comprising (A) (i) one or more of Forms I-VI of SN AC and/or (ii) amorphous SNAC. , and (B) an active agent, such as heparin. According to aa preferred embodiment, the pharmaceutical composition comprises at least aboust 20, 30, 40, 50, 60, 70, 80, 90, 9+5, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9% by weight of on_e of

Forms I-VI of SNAC or amorphous SNAC, based wmpon 100% total weight of SNAC in the pharmaceutical composition. According to another preferred embodiment, the pharmaceutical composition comprises at least aboust 20, 30, 40, 50, 60, 70, 80, 90, 9+5, 96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.77, 99.8, or 99.9% by weight of on_e of

Forms I-VI of SNAC, based upon 100% total weiglat of crystalline SNAC in the pharmaceutical composition.

[6] Yet another embodiment of th_e invention is a method for administering or facilitating the delivery of an actives agent in an animal (such as a hurman) by administering the pharmaceutical composition of ~ the present invention. :

[7] Yet another embodiment is a mmethod of treating thrombosis in a_n animal (such as a human) in need thereof by orally sadministering an anti-thrombosis effective amount of the pharmaceutical composition of the present invention comprisirg heparin.

Co t (8] Yet another embodiment is a method of preparing F7orm I of SNAC comprising the step of hea ting Form III, V, or VI of SNAC or a mixture - thereof to at least 50 °C (but preferably less than [10° C) for a time sufficient to form ForrmI of SNAC.

[9] Yet another embodiment is a method of preparing E==orm I of SNAC

S comprising the step of heating amorphous SNAC at from about 30 to abosut 90° C, and preferably from about 40 to about 80° C, for a time sufficient to form Form I of SNAC.

[10] Yew another embodiment is a method of preparing “Form I of SNAC comprising the step of lyaophilizing any form of SNAC other than Form WN to yield Form I.

For example, the methodu can include lyophilizing one or more of Forms. II-VI of SNAC and/or amorphous SNAC 10 yield Form I.

[11] Ye=tanother embodiment is a pharmaceutical compoosition, such as a tablet, comprising a mill ed (e.g., ball milled) or directly compressed mid xture of Form I of

SNAC and at least one amctive agent and/or pharmaceutically acceptable additive (such as those described below). The pharmaceutical composition can be prepar—ed by milling (e.g., ball milling) or compression (e.g., direct compression) of a mixture of Form I of SNAC and at least one active a_gent and/or pharmaceutically acceptable additiwe.

[12] Yet another embodiment is a method of preparinzg Form II of SNAC comprising the step of crying (e.g., tumble drying) a solvate (e.g., an ethanol solvate or methanol solvate) of SIAC without agitation and exposing the dried S"INAC to moisture for a sufficient time to yield Form II of SNAC. Preferably, the drying an.d exposure steps are performed in a closed econtainer. The dried SNAC may be stored ina moist environment to cause conversion of amy remaining SNAC, which is not Form II SNA-C, to Form II.

[13] “Yet another embodiment is a pharmaceutical co-xmposition, such as a tablet, comprising a directly compressed mixture of Form IT of SNACT and at least one

' Y. active azgent and/or pharmaceutically acceptatole additive (such as those described below).

The phas rmaceutical composition can be prepaared by compression (e.g., direct Compression) of a mixx ture of Form II of SNAC and at least one active agent and/or pharmaceutically acceptalole additive.

[14] Yet another embodimermt is a method of preparing Form L1I of SNAC compris ing the step of exposing Form I, II, I'W, V, or VI of SNAC or a mixture thereof to an envir-onment having a relative humidity of 75%, 80%, 85%, 90%, or greater, for a sufficiernt time to yield Form III.

[15] Yet another embodimemt is a method of preparing Form I' II of SNAC comprising the step of exposing amorphous SINAC to moisture (i.e., an enviromment having a relativee humidity greater than 0% and prefemrably greater than 5 or 10%) for a_ sufficient time to ye/ield Form III.

[16] Yet another embodiment is a method of preparing Form III of SNAC comprising the step of wet granulating Form I, II, IV, V, or VI of SNAC or amorphous

SNAC o ra mixture thereof (with or without o=-ne or more active agents and/or pharmac eutically acceptable additives (such as. those described below)) for a suf~ficient time to produce Form III. According to one embodiment, Form I of SNAC is wet gmranulated.

[17] - Yet another embodimenat is a method of preparing Form INI of SNAC comprisi ng the step of exposing Form V or VH of SNAC or a mixture thereof to- an environment having a relative humidity of 30%%, 35%, 40%, 50% or greater, fo ra sufficient time to yield Form III.

[18] Yet another embodiment is a method of preparing Form INI of SNAC comprising the step of exposing Form VI of SINAC to an environment having a -relative humidity of 10%, 20%, 30% or greater, for a sufficient time to yield Form III.

[19] Yet another embodiment is a method of prepar-ing Form III of SNAC comprising the step of crystallizing SNAC from water.

[20] Yet another embo-diment is a method of preparing Form III of SNAC comprising the step of wet granulating FForm I of SNAC for a sufficie=nt time to produce FormIIl

[21] Yet another embosdiment is a pharmaceutical ccomposition, such as a tablet, comprising a directly compressed mixture of Form III of SNA_C and at least one active agent and/or pharmaceutically acceptable additive (such as thosse described below).

The pharmaceutical composition can be prepared by compression (e.£=2., direct compression) of a mixture of Form III of SNAC and at least one active agent and/o r pharmaceutically acceptable additive.

[22] Yet another embodiment is a method of preparing Form IV of SNAC comprising the step of heating Form 1, IN, III, V, or VI of SNAC or ama mixture thereof to a temperature between about 110 or 150° & and the melting point of SNJAC (e.g., at 150 or 170° C) for a sufficient time to yield Form IV,

[23] Yet another embodiment is a method of preparimng Form V of SNAC comprising the step of crystallizing SNA C from a methanol solution a_t a relative humidity of at least 30, 40, or 50%. Preferably, t he methanol is substantially aor completely free of water. Without being bound by any part icular theory, it is believed thmat the methanol solvate exchanges methanol for atmosphesric water over time resulting in the methanol- water solvate of Form V. For example, Form V may be prepared by preparing a saturated solution of SNAC (e.g., Form I-IV or VX of SNAC or a mixture there=of) in methanol at a relative humidity of at least 30, 40, or 53%, and cooling the solution, e.g., to room

1 ‘¢ tempera ture or lower (such as in an ice bath). The resulting precipitate can be filte red and dried.

[24] Yet another embodiment is a method of preparing Form V of” SNAC comprising the step of equilibration of Forms I-IV or VI of SNAC with methanol. Preferabsly, the methanol solution is substantially or completely free of water. For example , Form V can be prepared by slurring any of Forms I-IV or VI or a mixture thereof in methanol at a relative humidity of at least 30, 40, or 50%, and maintaining the sl urried mixture .at ambient temperatures for a sufficierat time to form Form V (e.g., several days).

[25] Yet another embodiment= is a method of preparing Form VI of SNAC comprisi ng the step of crystallizing SNAC frorm an ethanol solution at a relative hurmnidity of at least 3-0, 40 or 50%. Preferably, the ethano_1 solution is substantially or completely free of water.. For example, Form VI can be prepa red by preparing a saturated solution of

SNAC (e=:g., Form I-V of SNAC or a mixture thereof) in ethanol at a relative humiclity of at least about 30, 40, or 50% and cooling the s=olution to room temperature or lower .

[26] Yet another embodiment is a method of preparing Form VI of SNAC comprisirng the step of slurring any of Forms I- V in ethanol at a relative humidity of at least 10, 20, 0-xr 30%. Preferably, the ethanol is subsstantially or completely free of water. For example, Form VI can be prepared by adding a_ny of Forms I-V to ethanol to form a precipitatee, and maintaining the slurried mixturee at ambient temperatures for a suffic dent time to foerm Form VI. [27) Yet another embodiment ms a method of preparing amorphous SNAC by dehydrating Form III of SNAC (e.g., in a vamcuum) for a sufficient time to form amorphous s SNAC.

Brief Description of the Drawings

[28] Figures 1,6, 1 1, 16, 21, 26, and 43 are X-ray gpowder diffractograms (XRPDs) of Forms I-VI of SNAC an_d amorphous SNAC (containing approximately 10%

Form III of SNAC), respectively, as prepared in Examples 1-6 and 14. [291 Figures 2, 7, 122, 17, 22, 27, and 44 are differemtial scanning calorimetry (DSC) analyses of Formss I-VI of SNAC and amorphous SNAC (containing approximately 10% Form III of SNA CO), respectively, as prepared in MExamples 1-6 and 14.

[30] Figures 3, 8, 123, 18, 23, 28, and 45 are thermo_gravimetric analyses (TGAs) of Forms I-VI of SNAC and amorphous SNAC (containing approximately 10%

Form III of SNAC), respectively, as prepared in Examples 1-6 and 14-.

[31] Figures 4,9, 14, 19, 24, 29, and 46 are FTIR sgpectra of Forms I-VI of SNAC and amorphous SNAC (comtaining approximately 10% Form III of SNAC), respectively, as prepared in Examples 1-6 and 14.

[32] Figures 5, 10, 15, 20, 25, 30, and 47 are moistiare adsorption/desorption spectra of Formas I-VI of SNAC and amorphous SNAC (containing approximately 10% Form III of SNA), respectively, as prepared in E=xamples 1-6 and 14.

[33] Figures 31 and 32 are graphs of the plasma hepaarin concentrations in cynos monkeys versus time after oral administration of capsules of Fomrm I or III of SNAC and heparin as prepared in Example 7.

[34] Figure 33 is a gcraph of the plasma heparin concesntrations in cynos monkeys versus time after oral admin -istration of capsules of Form I or III of SNAC and heparin as prepared in Example 7.

[35] Figures 34 and 35 are graphs of the plasma haeparin concentrations in cynos monkeys versus time after oral administration of capsules of Form I or III of SNAC and heparin as preparecd in Example 8.

[36] Figure 36 is a graph of the plasma heparin cc>ncentrations in cynos monkeys versus time after oral administration of capsules of Form I or III of SNAC and heparin as prepared in _Example 8. {371 Figure 37 is a graph of the amount by weightt of a pellet of Form I or

III of SNAC dissolved over 15 minutes in deionized water at 37° CZ (Example 9).

[38] Figure 38 is a graph of the amount by weight= of a pellet of Form I,

II, II, or IV of SNAC dissolved over 15 minutes in deionized wate=r at 37° C (Example 9). [391 Figure 39 shows XRPDs of Form I of SNACT before and after ball milling (Example 11).

[40] F=igure 40 shows XRPDs of Form I of SNAC= before and after wet granulation (Example 1 2).

[41] Figure 41 shows XRPDs of Form I of SNACZ before and after compression (Example 13).

[42] Figure 42 shows XRPDs of Form III of SNA _C before and after compression (Example 13).

Detaile=d Description of the Invention

Definit=ions

[43] The term “polymorpha” refers to crystallographiecally distinct forms of a subst=ance.

[44] The term “hydrate” a s used herein includes, but is not limited to, (i) a subst. ance containing water combined in the molecular form and (ii) a crystalline substarce containing one or more molecules of water of crystallizatior or a crystalline materizal containing free water.

[45] The term “SNAC” ass used herein refers to mon.osodium N-[8-(2- hydroxzybenzoyl)amino] caprylate. Unless otherwise noted, the term “*SNAC” as used herein refers to all polymorphs of SNAC.

[46] The term "SNAC 1/3 hydrate” as used herein refers to a crystalline form of SNAC in which one molecule of w ater is associated with three molecules of

SNAC .

[47] The term “SNAC trilhydrate” as used herein refZers to a crystalline form cof SNAC in which three molecules of® water are associated with each molecule of

SNACT. f48) The term “solvate” as used herein includes, bu is not limited to, a molecwmalar or ionic complex of molecules ox ions of a solvent with molecules or ions of

SNACT. The term “co-solvate” as used herein includes, but is not limited to, a molecular or ionic complex of molecules or ions of two or more solvents with mol=ecules or ions of

SNACC.

[49] The term “delivery agent” as used herein refers to SNAC, including its cry~ stalline polymorphic forms.

[50] An “effective amount of drug” is an amount of the active agent (e.g., heparin) which is effesctive to treat or prevent a condition in a living : organism to whom it is administered over some period of time, e.g., provides a therapeutic effect during a desired dosing interval. Effective doses will vary, as recognized by those s Killed in the art,

S depending on the rout e of administration, excipient usage, and the peossibility of co-usage with other agents for ®reating a condition.

[51] The term “treat”, “treating”, or “treated” refeers to administering an active agent with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect a ¢ ondition (e.g., a disease), the symptoms of thes condition, or the predisposition toward the condition.

[52] An “effective amount of delivery agent” is arm amount of the delivery agent which promotes the absorption of a desired amount of the act®i ve agent via any route of administration (such as those discussed in this application includi .ng, but not limited to, the oral (e.g., across =a biological membrane in the gastrointestinal tract), nasal, pulmonary,

I5 dermal, vaginal, and/or ocular route}.

[53] The term “heparin” as used herein refers to a_1l forms of heparin, including, but not limited to, unfractionated heparin, heparinoids, d.ermatans, chondroitins, low molecular weightz heparin (e.g., tinzaparin (including tinzaparir sodium)), very low molecular weight hep arin, and ultra low molecular weight heparin. A preferred type of heparin is unfractionated heparin, such as heparin sodium (e.g., hegparin sodium USP). The term “low molecular weight heparin” generally refers to heparin in = which at least 80% (by weight) of the heparir has a molecular weight of between about 3020 and about 9000 daltons. Non-limitingz examples of low molecular weight heparin ir-iclude tinzaparin, enoxaprin, and daltipzarin. Tinzaparin has been approved by the FI DA for the treatment of

WO =2005/107462 PCT/US2005/016126 acute symptomatic deep vein thrombosis with or without pulmonary enmbolism when adminisstered in conjunction with warfar®n sodium. The sodium salt of tinazaparin is availabMe under the trademark Innohep™ from Pharmion Corporation o f Boulder, CO. The term “wery low molecular weight hepari n” generally refers to heparin i n which at least 80% (by wem ght) of the heparin has a molecular weight of between about 15030 and about 5000 daltons . Non-limiting examples of very low molecular weight heparin include bemiparin.

The ter—m “ultra low molecular weight heparin” generally refers to heparin in which at least 80% (bey weight) of the heparin has a melecular weight of between abo—ut 1000 and about 2000 daltons. Non-limiting examples of ultra low molecular weight he :parin include fondipamrinux.

[54] The term “insulin > refers to all forms of insulin, including, but not limited to, naturally derived insulin and synthetic forms of insulin, suchh as those described in U.S. Patent Nos. 4.421.685, 5,474,978, and 5.534.488, each of whrich is hereby incorporated by reference in its entirety .

[55] The term “AUC” as used herein, means area uncer the plasma concen-tration-time curve, as calculated by the trapezoidal rule over the= complete dosing interva 1, e.g., 24-hour interval.

[56] The term “mean” , when preceding a pharmacokinetic value (e.g., mean Feak) represents the arithmetic meean value of the pharmacokinetic value unless otherwise specified.

[57] As used herein, tlhe term “about” means within M0% of a given value, preferaa bly within 5%, and more preferably within 1% of a given value=. Alternatively, the term “azabout” means that a value can falll within a scientifically accepta_ble error range for that type of value, which will depend on how qualitative a measurement can be g-iven the available tools.

Anhydrous SNAC Form I

[58] Crystalline polymorph Form I of SNAC is anhydrous. Form 1 is stable at room temperature, and does not change crystal form when subjected to rnilling (e.g., ball milling) or compression (e.g., direct compression). Form I, however, does convert to Form III when w et granulated with a sufficient amount of water for a sufficient amount of time. According to differential scanning calorimetry (DSC), Form h-as a melting point onset at about 198° C (see Figure 2). Form I of SNAC has an XRFPD pattern substantially identical to that shown in Figure 1. Characteristic XRPD peak locat-ions (expressed in degrees 20 = 0.2, 0.1, 0.05, or 0.01° 26) and d-spacing for Form HN are provided in Table 1 below. The XRPD peak locations marked “(U)” in Table 1 are unique to Form I. For example, the peak at 2.98° 26 + 0.2, 0.1, 0.05, or 0.01° 24 is wmnique to

Forml.

Tablel

Characteristic XRPD Peaks (expressed in degrees 26) of Formm I of SNAC

Degrees 26+ 0.2° 26 a (A) 2.98 (U) 29.59

[59] Form I may be prepared by the procedure described in Example 1

S below.

[60] Form I may also be prepared by heating Form IIT, V, or Vl or a mixture ttmereof to a temperamure of at least 50° C (but preferably less tlaan 110° C).

[61] Form I may further be prepared by heating amorp_hous SNAC at from about 30 tco about 90° C, and preferably From about 40 to about 80° C, for a time sufficient to form Fomrm I of SNAC.

[62] Another method off preparing Form I is by lyophZilizing any form of

SNAC oth:er than Form I to yield Form X. For example, one or more cf Forms II-VI of

SNAC ancd/or amorphous SNAC can be lyophilized to yield Form I.

[63] The present invent ion also provides a pharmaceu-tical composition containing: Form I of SNAC in which les.s than 90, 80, 70, or 60% of the SNAC is crystalline (based on 100% total weight of SNAC).

[64] The present invemtion also provides a pharmaceutical compmosition, such as a tablet, comprising a milled (e=.g., ball milled) or directly compressed m_ixture of

Form I of SNAC and at least one actives agent and/or pharmaceutically acceptable additive (such as those described below). Prefe=rably, the pharmaceutical composition (or milled or directly compressed mixture) includes zat least 50, 60, 70, 80, 90, 95, 96, 97, 98... or 99% by weight of Form I based on the total weight of SNAC in the pharmaceutical composition (or milled or directly compressed mixture).

SNAC Hydrate Form II

[65] Crystalline polynmorph Form II is a hydrate of SNAC. Without being bound by any particular theory, the inv entor theorizes that Form II is a 1/3 hydra_te (i.e., it has approximately 1 mole of water per 3 moles of SNAC (also referred to as SNAC 1/3 hydrate)). Form II is stable at room temperature. According to DSC, Form II has a melting point onset at about 199° C (seee Figure 7). Form II of SNAC has an XR_PD pattern substantially identical to that shown in XFigure 6. Characteristic XRPD peak locations (expressed in degrees 20 + 0.2, 0.1, 0.05, or 0.01° 26) and d-spacing for Form I are provided in Table 2 below. The XRPID peak locations marked “(U)” in Table 2 zare unique to Form II. For example, the peaks at 3.29, 11.96, and 17.76° 26 + 0.2, 0.1, 0-05, or 0.01° 280 are unique to Form II.

Wea0 2005/107462 E2>CT/US2005/016126

Table 2

Characteristic XRPD Peaks (expressed in degrees 28) of Form II of SNAC

Degmrees 260 Degrees 26 Degrees 2&7 +0.2°29 d © +0.2° 20 d@ +0.2°260 d@ 3.20 (U) | 26.83 19.44 26.20 (U) 5.78 (U) | 15.27 20.16 (440 |26.48(U) 6.56 (U) | 13.46 20.72 (OF) 26.88 (U) =o 22.96 0) nw)

[66] Form II of SNAC may be prepared by drying (e.gz ., tumble drying) a solvamte (e.g., an ethanol solvate or methanol solvate) of SNAC without zgitation and expossing the dried SNAC to moisture for a sufficient time to yield Form II of SNAC.

Preferably, the drying and exposure steps are performed in a closed container. The expossure step may be performed subsequent to the drying step. The drieed SNAC may optiomnally be stored in a moist environament (e.g., at ambient conditions or in a humid envireonment (e.g., a relative humidity «of 10 or 20% or more)) to cause sconversion of any remam ning SNAC, which is not Form IX SNAC, to Form II. An ethanol! solvate of SNAC may boe prepared by the procedure described in Example 2.

SNAC Elydrate Form III

[67] Crystalline polymorph Form IIT is a hydrate of SNAC. Without being bound by any particular theory, the inventor th eorizes that Form III is a trihydrate (i.e., it Bas approximately 3 moles of water per mole of SNAC (also referred to as SNACC trihydra—te)). Form III is stable at room temperature, and does not change crystal form when subjected to compression (e.g., direct compression). According to differential scanning calorimetry (DSC), Form III has a melting gpoint onset at about 198° C (see Figure 12). Fosrm III of SNAC has an XRPD pattern substamntially identical to that shown in

Figure 1L 1. Characteristic XRPD peak locations (expressed in degrees 26 + 0.2, 0.1, 0.005, or 0.01°® 26) and d-spacing for Form III are provided in Table 3 below. The XRPD pealx locationss marked “(U)” in Table 3 are unique to Forrm III. For example, the peaks at 6.459, 13.58, aand 16.80° 28 + 0.2, 0.1, 0.05, or 0.01° 26 are unique to Form III.

Table 3 «Characteristic XRPD Peaks (expressed in deg=rees 26) of Form II of SNAC

Deg rees 20+ 0.2° 26 d (A) Degrees=s 20+ 0.2° 26 d (A) 6.69 (U) 13.20 20.56 (U) 13.58 (U) 21.60 (U) 6410 2560) 19.92 (U) 3001 W)

EE = 016 [4490 NOON

[68] Form III may be prepared by expoesing Form I, II, IV, ™V, or Vl or a mixture thereof to am environment having a relative humidity of 75%, 85%, 90%, or greater, for a sufficient time (e.g., seven days or longer) to yield Form III. F=or example,

Form III can be prep-ared by exposing any of Forms I, IK, or IV-VI to an envi ronment

S having a relative humidity of 75% or greater for at least seven days (e.g., until the moisture content of the materi:al is at least about 15% w/w). If th .e moisture content of ~ the material is significantly greater than 15% w/w, the material is praeferably dried at ambient conditions until the material hass a moisture content of about 15% w/w.

[69] Form III may also be prepared by exposing amorphous SNAC to moisture (i.e., an environment having a relative humidit—y greater than 0% anc preferably greater than 5 or 102%) for a sufficient time to yield Form III.

[70] Form III may also be prepared by wet granulation (aque=ous granulation) of Fornm I, II, IV, V, or IV of SNAC or ammorphous SNAC or a mmixture thereof. According ®o one embodiment, Form I is wet gzranulated. The Fornm III produced may subsequently dimrected (e.g., at 50° C) to obtain For:m I of SNAC again.

[71] Yet another method of preparing F=orm III is by exposirag Form V or

VI of SNAC or a mixture thereof to an environment having a relative humidisty of 30%, 35%, 40%, 50%, or greater, for a sufficient time to yield Form III. Another- method of preparing Form III iss by exposing Form VI of SNAC or— a mixture thereof to an environment having -a relative humidity of 10%, 20%, 3 0%, or greater, for a sufficient time to yield Form INI. [72) Form III may also be prepared by crystallizing SNAC ffrom water.

Crystals formed may= be isolated by, for example, filterimng and drying at amb. ient conditions. Preferatsly, drying is performed at less than 40 or 35° C.

[73] The present invention also provides a pharmaceutical composi#tion, such as a tablet, comprising a directly compressecd mixture of Form III of SNAC anc at least one active agent and/or pharmaceutically acceptable additive (such as those des<cribed below). Preferably, the pharmaceutical composit ion (or directly compressed mixtur €) includes at least 50, 60, 70, 80, 90, 95, 96, 97, M8, or 99% by weight of Form III boased on the total weight of SNAC in the pharmaceutical ¢ omposition (or directly compressecd mixture).

Anhydrous SNAC Form IV

[74] Crystalline polymorph Formm IV of SNAC is anhydrous. ForrmIV is stable at room temperature. Furthermore, Form 1V is less soluble in acetonitrile anid more thermodynamically stable than Form I at ambient conditions. According to differermtial scanning calorimetry (DSC), Form IV has a melting point onset at about 199° C (se=e Figure 17). Form IV of SNAC has an XRPD pattern sumbstantially identical to that shown mn

Figure 16. Characteristic XRPD peak locations (expressed in degrees 26 + 0.2, 0. 1, 0.05, or 0.01° 26) and d-spacing for Form IV are prowided in Table 4 below. The XRPIL peak locations marked “(U)” in Table 4 are unique to Form IV. For example, the peaks. at 8.61, 17.04, and 23.28° 28 + 0.2, 0.1, 0.05, or 0.01° 28 are unique to Form IV.

Table 4

Characteristic XRPD Peaks (expressed in degrees 26) of Form IV of SNAC

Form IV may be prepared by heating Form I, II, III, V or VI of SNAC or a mixture thereof tc» a temperature between about 110 or 150° CC and the melting point of SNAC_ for a sufficient time to yield Form IV. For example, Forma II of SNAC may be heated (su ch as in a dry Oven) to a temperature greater than the transition temperature of the desolvasted material ®but lower than the melting temperature of SNNAC (e.g., dehydration occurs &ata heating rate of 10° C/min with onset at about 130-14€0° C) until Form IV is formed (e.g., for sever al hours). After formation, Form IV can be cooled and recovered.

[75] The present invention also prowides a pharmaceutical compositZion containirmg Form IV of SNAC in which at least 50, 6€0, 70, 80 or 90% of the SNAC is crystallirae (based on 100% weight of SNAC).

Methanol-Water Co-solvate of SNAC Form V

[76] Crystalline polymorph Form V of SNAC is a methanol-water co- solvate ( approximately 0.8 moles of methanol and 2 moles of water per 1 mole of SINAC).

Accordimg to differential scanning calorimetry (DSC), Form V has a melting point Onset at about 197° C (see Figure 22). Form V of SNAC has an XRPD pattern substantially identi cal to that shown in Figure 21. Characteristic XRPD peak locations (expressed in degre es 20 + 0.2, 0.1, 0.05, or 0.01° 26) and d-spacing for Form V are provided in Table below. The XRPD peak locations marked “(U)” in Table 5 ares unique to Form V. For 5 example, the peaks at 6.59, 9.96, 10.86, 13.87, 17.29, and 19.922° 28 £0.2, 0.1, 0.05, or 0.01° 26 are unique to Form V.

Table §

Characteristic XRPD Peaks (expressed in degrees 26) off Form V of SNAC

Degrees 20 Degrees 26 Degorees 26 +0_.2°26 d@ +0.2°260 d@ + (09.2° 26 d@ 6.24 U 14.15 21.35 U 32 13 U 6.59 U 13.39 22.68 U 33.03 U 10.86 U 2.16 U 35 4 17.90 26.13 3649 U 19.920 | 445 | 30480 392.03 U

EXTH IRENE ECT ETE \ 20.44 U 4.34 31.52 U 22 Him - ;-H-HHDnnean [771 Form V may be prepared by crystallizatiora of SNAC (e.g., Form I-

IV or VI of SNAC or a mixture thereof (e.g., a mixture of Formas 1 and III)) from a methaanol solution at a relative humidity of at least about 30, 40, or 50%. Preferably, the methzanol solution is substantially free or completely free of wate=r. For example, Form V may be prepared by preparing a saturated solution of SNAC (e.g ., Form I-1V or VI of

SNAC or a mixtumre thereof) in methanol at a relative hurmidity of at least about 30, 40", or 50%, and cooling the solution, e.g., to room temperatures or lower (such as in an ice bath).

The resulting prec=ipitate can be filtered and dried. [781 Form V may also be prepared by equilibration of Forms I-IV or— VI of SNAC with me=thanol. Preferably, the methanol is substantially or completely free of water. For example, Form V can be prepared by slurring any of Forms I-IV or VI or— a mixture thereof im methanol at a relative humidity of at le2ast 30, 40, or 50% (e.g., to cause precipitation of th e SNAC out of solution), and maintain#ing the slurried mixture at ambient temperatures for a sufficient time to form Form V (e.g., several days). Preferably, arm excess of methanol (i.e., the molar ratio of methanol to SNAC is greater than 1) is useed.

The resulting soliad may be recovered, e.g., by vacuum filtration and air-drying.

Ethanol-Water Co-solvate of SNAC Form VI

[79] Crystalline polymorph Form VI ofS SNAC is an ethanol-water ceo- solvate (approximately 0.6 moles of methanol and 2 mol es of water per 1 mole of SN_AC).

According to differential scanning calorimetry (DSC), Form VI has a melting point omnset at about 197° C (see= Figure 27). Form VI of SNAC has ara XRPD pattern substantially identical to that skhown in Figure 26. Characteristic XRE?D peak locations (expressed in degrees 26 + 0.2-,0.1, 0.05, or 0.01° 26) and d-spacing for Form V are provided in Table 6 below. The XIRPD peak locations marked “(U)” in Taable 6 are unique to Form VI_. For example, the peak<s at 9.60, 10.43, 12.68, and 16.58° 2e9 + 0.2, 0.1, 0.05, or 0.01° 220 are unique to Form WI.

Table 6

Characteristic XRPD P-caks (expressed in degrees 28) of Form VI o fSNAC

Degrees 26 | “Degrees 20 Degrees 26 +0.2°26 d@ | 02°20 d +£0.2° 20 d @) 5.68 U 15.55 | 1896U | 468 | 2556U 6.35U 13.91 | 19.37 EEN 26.98 U

[80] Form VL may be prepared by crystallization of SNAC (e.g., Forms I-

Vor a mixture thereof) from a_n ethanol solution at a relative humidity of at least about 30, 40 or 50%. For example, Form VI can be prepared by preparing a saturate-d solution of

SNAC (e.g., Form I-V of SNAAC or a mixture thereof) in ethanol at a relative humidity of at least about 30, 40, or 50% and cooling the resulting solution to room termmperature or lower (e.g., in an ice bath). T he resulting precipitate can then be filtered ard dried.

[81] Form VII may also be prepared by slurring any of For-ms I-V in ethanol at a relative humidity of at least about 10, 20, or 30%. For examplee, Form VI can be prepared by adding any of BForms I-V to ethanol to form a precipitate, amd maintaining the slurried mixture at ambien® temperatures for a sufficient time to form Form VI (e.g.,

several days). Thea resulting solid may be recovered, e.g., By vacuum filtration and air- drying.

Amorphous SNACT [828 Amorphous SNAC is unstable at ambzent conditions and converts tC

Form III upon exp osure to humidity. Amorphous SNAC can be prepared by dehydrating

Form III of SNAC (e.g., in a vacuum) for a sufficient time to form amorphous SNAC.

Amorphous SNACT can also be prepared by dehydrating Form V or VI of SNAC (e.g., in. a vacuum) for a sufficient time to form amorphous SNAC. [83@ The crystals prepared by any of the aforementioned procedures mays be recovered by ary method known in the art.

Active Agents

[84] Active agents suitable for use in the present invention include biologically active agents and chemically active agents, including, but not limited to, pesticides, pharma cological agents, and therapeutic agents.

[85] Suitable biologically and chemically a_ctive agents include, but are maot limited to, proteinss; polypeptides; peptides; hormones; polysaccharides, muco- polysaccharides an.d particularly mixtures of muco-polysaccTharides; carbohydrates; lipids = small polar organic molecules (i.e. polar organic molecules having a molecular weight of 500 daltons or less. ); other organic compounds; and particulzarly compounds which by themselves do not pass (or which pass only a fraction of the: administered dose) through time gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzyme s in the gastro-intest inal tract; or any combination thereof.

[86] Further examples of suitable biologically active agents includ-€, but amre not limited to, the following, including synthetic, naatural or recombinant source=s tiaereof: growth hormones, including human growth ho rmones (hGH), recombinant human gmowth hormones (thGH), bovine growth (hGH), bovinee growth hormones, and pomcine gmowth hormones; growth hormone-releasing hormones ; growth hormone releasing factor (e.g., GRF analog g); interferons, including a, B and y; interleukin-1; interleukin-2 ; irasulin, including porcine, bovine, human, and human recombinant, optionally haviing counter ions including zinc, sodium, calcium and ammo-nium; insulin-like growth factor, imcluding IGF-1; heparin, including unfractionated hepa rin, heparinoids, dermatans ,

chondroitins, low molecular weight heparin, very low molecular weight heparin ancl ultra losw molecular weight heparin; calcitonin, including salmon, eel, porcine and humar; er-ythropoietin; atrial naturetic factor; antigens; monoclosnal antibodies; somatostatirm ; pr-otease inhibitors; adrenocorticotropin, gonadotropin releasing hormone; oxytocin le utinizing-hormone-releasing-hormone; follicle stimulat-ing hormone; glucocerebrossidase;

th.rombopoietin; filgrastim; prostaglandins; cyclosporin; vasopressin; cromolyn sodium (s«odium or disodium chromoglycate); vancomycin; desfesrrioxamine (DFO); bi sphosphonates, including ibandronate, alendronate, tiluadronate, etidronate, clodrozmate, pamidronate, olpadronate, and incadronate, and pharmacCeutically acceptable salts tha ereof (e .g., ibandronate sodium); gallium salts (such as galliurm nitrate, gallium nitrate nonahydrate, and gallium maltolate); acyclovir and pharmaceutically acceptable salt=s theereof (e.g., acyclovir sodium); parathyroid hormone (PTH), including its fragments; anti- mizgraine agents such as BIBN-4096BS and other calcitoenin gene-related proteins an.tagonists; antimicrobials , including antibiotics (includ-e gram-positive acting, ba_cteriocidal, lipopeptidal and cyclic peptidal antibiotics , including daptomycin), an&i-

bacterials and anti-fungal agents; vitamins; analogs, fragments, mimetics or polyethylene glycol (PEG)-modified derivatives o-f these compounds; or any combinaticon thereof.

[87] According to cone embodiment, the active agent is it andronate or a pharmaceutically acceptable salt thereof (e.g., ibandronate sodium). AccOrding to another embodiment, the active agent is a gallium salt, such as gallium nitrate or gallium nitrate nonahydrate. According to yet another embodiment, the active agent is acyclovir or a pharamceutically acceptable salt ther—eof (e.g., acyclovir sodium). According to yet another embodiment, the active agent is heparin. According to yet another embodiment, the active agent is insulin.

Pharmceutical Compositions

[88] The pharmacewutical composition is preferably in sol3d form and may be formed into a solid dosage form. The solid dosage form can be a capsule, tablet or particle, such as a powder or sachet. The powder may be in the form of aa sachet that is mixed with a liquid and administerecl. The solid dosage form may also be= a topical delivery system, such as an ointment, cream or semi-solid. The solid dosage form contemplated may include a sustained release or controlled release system— Preferably, the solid dosage form is for oral adminisstration.

[89] The powder m.ay be packed into capsules, or pressecd into tablets, used in powder form, or incorporated into an ointment, cream or semi-solid. Methods for forming solid dosage forms are well known in the art.

[90] The amount of delivery agent in the solid dosage for-m is a delivery effective amount and can be determired for any particular compound or bi_ologically or chemically active agent by methods known to those skilled in the art.

[91] Following administration, the active agent ir the dosage unit form is taken up into circulation. The bioavailability of the active agent is readily assessed by measuring a known pharmacological activity in blood, e.g. an increase in blood clotting time caused by heparin, or a decrease in circulating calcium levels. caused by calcitonin.

Alternately, the circumlating levels of the active agent itself can be rmeasured directly.

[92] The solid dosage form may include pharmaceutically acceptable additives, such as excipients, carriers, diluents, stabilizers, plasticizers, binders, glidants, disintegrants, bulking agents, lubricants, plasticizers, colorants, fillm formers, flavouring agents, preservatives _, dosing vehicles, surfactants, and any combimation of any of the foregoing. Preferably, these additives are pharmaceutically acceptable additives, such as those described in Re=mington's, The Science and Practice of Pharemacy, (Gennaro, A.R., ed., 19th edition, 19935, Mack Pub. Co.) which is herein incorporated by reference.

[93] Suitable binders include, but are not limited to, starch, gelatine, sugars (such as sucro:se, molasses and lactose), dibasic calcium phesphate dihydrate, natural and synthetic gums (ssuch as acacia, sodium alginate, carboxymethyl cellulose, methyl cellulose, polyvinylpyyrolidone, polyethylene glycol, ethylcellulose, and waxes.

[94] Suitable glidants include, but are not limited to, talc, and silicon dioxide (silica) (e.g, fumed silica and colloidal silicon dioxide).

[95] Suitable disintegrants include, but are not limnited to, starches, sodium starch glycolate, crosecarmellose sodium, crospovidone, clays, celluloses (such as purified cellullose, methylcellmilose, sodium carboxymethyl cellulose), algiraates, pregelatinized corn starches, and gums (s~uch as agar, guar, locust bean, karaya, pectira and tragacanth gums).

A preferred disintegraant is sodium starch glycolate.

[96] Suitable bulking agents include, but are n-ot limited to, starches (such as rice starch), micmrocrystalline cellulose, lactose (e.g., lactose monohydrate), sucrose, dextrose, mannitol, calcium sulfate, dicalcium sulfate, and trica_lcium sulfate.

[97] Suitable lubricants include, but are not lirmited to, stearic acid, stearates (such as calcium stearate and magnesium stearate), tale, boric acid, sodium benzoate, sodium acetate, sodium fumarate, sodium chloride, peolyethylene glycol, hydrogenated cottoraseed, and castor oils.

[98] Suitable surfactants include, but are not li_mited to, sodium lauryl sulfate, hydroxylate=d soy lecithin, polysorbates, and block coposlymers of propylene oxide and ethylene oxide.

Delivery Systems

[99] The amount of active agent used in a pharmaceutical composition of the present invention is an amount effective to accomplish the purpose of the particular active agent for the target indication. The amount of active agemt in the compositions typically is a pharm acologically, biologically, therapeutically, o r chemically effective amount. However, the amount can be less than that amount wh en the composition is used in a dosage unit foram because the dosage unit form may contain_ a plurality of delivery agent compound/actzive agent compositions or may contain a div-ided pharmacologically, biologically, therapeutically, or chemically effective amount. T he total effective amount can then be adminis tered in cumulative units containing, in total _, an effective amount of the active agent.

[100] The total amount of active agent to be use=d can be determined by methods known to those skilled in the art. However, because time compositions of the invention may deRiver active agents more efficiently than otzher compositions or compositions con®aining the active agent alone, lower amoants of biologically or chemmically active agents thanu those used in prior dosage unit forms or delivery systems can be administered to time subject, while still achieving the same t>lood levels and/or therapeutic effects. [1O1] Generally, the weight ratio of deliver—y agent to active agent raenges from about 0.1:1 to about 1000:1 and preferably from about 1:1 to about 300:1. The weight ratio will wary according to the active agent and the particular indication for v=vhich the active agent iss administered. [LO?2] The presently disclosed delivery agerts facilitate the delivery o=f biologically and c=hemically active agents, particularly in oral, sublingual, buccal, intraduodenal, int-racolonic, rectal, vaginal, mucosal, pulmcnary, intranasal, and ocu lar systems. © [103] The compounds and compositions of the subject invention are Laseful for administering biologically or chemically active agents tO any animals, including tut not limited to birds stach as chickens; mammals, such as rodent:s, cows, pigs, dogs, cats, primates, and particularly humans; and insects.

[104] The compounds and compositions a.re particularly advantage.ous for delivering chemically or biologically active agents that would otherwise be destroyed or rendered less effesctive by conditions encountered before tlhe active agent reaches it=s target zone (i.e. the are a in which the active agent of the delivemry composition is to be released) and within the body of the animal to which they are administered. Particularly, the compounds and compositions of the present invention ar-e useful in orally admin _istering active agents, especially those that are not ordinarily orally deliverable, or those fomr which improved delivery is desired.

[105] The compositions comprising the compounds and active agermts have utility in the delivery of active agents to seelected biological systems and in an incre=ased or improved bioavailability of the active agernt compared to administration of the activ-e agent without the delivery agent. Delivery can toe improved by delivering more active age=nt over a period of time, or in delivering active agent in a particular time period (such as teo effect quicker or delayed delivery) or over a peri=od of time (such as sustained delivery). [106) Another embodimemt of the present invention is a method for the treatment or prevention of a disease or for— achieving a desired physiological effect, such as those listed in the table below, in an animaml by administering the composition of the present invention. Specific indications for activee agents can be found in the Physicians’ Desk

Reference (54™ Ed., 2000, Medical Econ:omics Company, Inc., Montvale, NJ), which is herein incorporated by reference. The active agents in the table below incluce their analogs, fragments, mimetics, and polyethylene glycol-modified derivatives.

Growth hormones, including humarm | Growth disorders growth hormones (hGH), recombinant human growth hormones (rhGH), bovine= growth hormones, and porcine growthm hormones; growth hormone-releasings hormones.

Interferons, including 0, 0 and 0. Viral infection, including chronic caracer and multiple sclerosis

Interteuin-1; interleukin 2.

Insulin, including porcine, bovine, human, | Diabetes and human recombinant, optionally havings counter ions including zinc, sodium. calcium and ammonium; insulin-like= growth factor, including IGF-1.

Active Agent Disease and Physiological Effect

Heeparin, including unfractionated heparin, | Thrombosis; prevention of blood he=parinoids, dermatans, chondroitins, low | coagulation meolecular weight heparin, very low meolecular weight heparin and ultra low meolecular weight heparin.

Calcitonin, including salmon, eel, porcine | Osteoporosis; diseases of thes bone amd human.

Atrial naturetic factor Vasodilation

M onoclonal antibodies To prevent graft rejection; ¢ ancer

Adrenocorticotropin High cholesterol (to lower clholesterol)

Gonadotropin releasing hormone Ovulatory disfunction (Cto stimulate ovulation)

Growth Hormone Releasing Factor (GRF) | stimulates the secretion o-f the growth “hormone

Oxytocin Tabor disfunction (to stimulate «contractions)

Le=utinizing-hormone-releasing-hormone; “Regulate reproductive functi=on follicle stimulating hormone

Gl wcocerebrosidase «Gaucher disease (to metabolize lipoprotein)

Thrombopoietin “Thrombocytopenia

Reduce infection in chemoth:erapy patients

Cy=closporin “Transplant rejection

Cromolyn sodium (sodium or disodium | .Asthma; allergies charomoglycate); vancomycin

Paxathyroid hormone (PTH), including its | ® steoporosis; diseases of thes bone fra_gments.

A antimicrobials, including antibiotics, arti- | Infection including gram-possitive bacterial beacterials and anti-fungal agents; graam- | infection positive acting, bacteriocidal, lipopepticial and cyclic peptidal antibiotics, a.nd imcludes daptomycin and analogues thereof

Bisphosphonates, including ibandrona. te, | Osteoporosis and Paget's di sease; Inhibits a lendronate, tiludronate, etidrona. te, | osteoclasts c lodronate, pamidronate, olpadronate, and imcadronate (Gallium salts (e.g., gallium nitrate) Treats or prevents hypercalcemia. Treats or prevents a disorder asssociated with excessive (or accelerated) loss of calcium from bone in a mammal (such as a human) by administering to the mammal an effective amount of the pharmaceutical formulation of the prese=nt invention.

Such disorders include, but zare not limited to, hypercalcemia, osteopenia, osteoporosis, bone destruaction due to metastasis from maligmmant tumors, hyperparathyroidism, rernal disease, iatrogenic disease (including= drug-induced diseases), and periodoratal disease.

Inhibits resorption or relea se of calcium from bone.

My cyclovir Treats virus infections, espwecially herpes infections such as herpes simplex 1 and 2 viruses (HSV 1, HSV 2), v-aricella zoster virus (VZV), cytomegalovirus (CMV) and

Epstein-Barr virus (EBV®, and other herpes virus infections (e.g_ feline herpes virus infections). Treats clinical conditions or symptoms whch are caused by the viruses enumemrated above, including herpetic karatitis, herpetic encaphalitis, cold sores and genital infections (caused by herpes simplex), chicken pox and shingles (caused by varicella zoster) and CMV -pneumonia and retinitis, particular-ly in immunocompromised patieznts including renal and bone marrow transplant patients amd patients with Acquired Imnune

Deficiency Syndrome (AIDS) by administering an effective amount of ~ the coemposition or dosage unit form of the present invention. Epstein-Barr virus (ECVB) causes infectious mononuclecsis, amd is also suggested as the causamtive agent of nasopharyngeal can.cer, imamunoblastic ~~ lymphoma, BurkZitt's lymmphoma and hairy leukoplakia.

[107] The following examples i llustrate the present invention withoust limitation. All percentages are by weight unless=s otherwise specified.

DSC

[108] The melting points cited. were determined by differential s canning calorimety (DSC). The quoted values were obotained with Perkin Elmer Pyris 1 ssoftware for Windows. The instrument was calibrated for temperature using the melting pe=oints of indium and zinc, and for enthalpy using the «enthalpy of fusion of indium. Cal: ibration checks were performed on a routine basis using an indium standard. Samples were sealed in an aluminum pan with a crimped lid that ha«d a tiny hole in it. The samples we=re then heated in a nitrogen atmosphere from 30 to 250°C at 10° C/min. Un-milled samplees were lightly ground with a mortar and pestle prior to analysis in order to improve thermal contact with the surfaces of the sample ‘pan.

XRPD

[109] The Powder X-Ray diffraction analysis was done using a Sh _imadzu

XRD-6000 powder diffractometer, available frosm Shimadzu Scientific Instruments, Inc. of

Columbia, MED. The instrument was calibrated usirag silicon powder, and the ecalibration was found to be correct when it was tested with an NIST #675 low-angle diffraction standard. Th e samples were illuminated with Cu Ka radiation (A = 1.54056 A). Un- milled sample=s were lightly ground with a mortar and pestle so that a samples could be prepared for ;analysis with a smooth, even, surface. ‘The diffraction pattern between 2 and 40° 26 was ussed as a fingerprint region to identify the crystal structure present in. the lots.

Thermogravi-metric Analysis (TGA)

[110] Thermogravimetric analysis of sodium 4-CNAB was condiacted using a Perkin-Elmeer TGA7 thermogravimetric analyzer with Pyris 1 for Windows< software.

The instrumerit was calibrated for temperature using the curie points of alumel znd nickel.

Samples were= heated in a nitrogen atmosphere from 30 to 300°C and the percent change in weight as a function of temperature was recorded. The un-milled lots were liglmtly ground with a mortar and pestle prior to analysis in order to decrease the effect of particle size and improve cont=ict with the inner surfaces of the platinuam sample holder.

Water Sorptiion-Desorption Behavior {1111 Sorption analysis was conducte-d using an SGA-100 Symme=tric Vapor

Sorption Ana lyzer (available from VTI Corporation. of Hialeah, Florida). The instrument was calibratecd using PVP and NaCl. Samples (othe x than solvates) were dried to constant weight at 60° C prior to analysis. Samples of solvates were not dried prior to te=sting. The equilibrium water content of the sample from 5% relative humidity (RH) to 95 % RH and then back dovwn to 5% RH was determined at 25°C.

FTIR

[112] FTIR was performed on a Perkin Elmer Spectrum BX FT-IR using

KBr discs. 1 mg of sample was dispersed in 150 mg KBr. The resolution was 4 cm” and 32 scans were averaged.

S

Example 1

Preparation for Form I of SNAC

[113] Form. I of SNAC was prepared as follows. T he free acid of SNAC (i.e. N-(8-[2-hydroxybenzo-yllamino)caprylic acid) was prepared by ti-ae method described in

Example 1 of International Publication No. WO 00/59863, which is Imxereby incorporated by reference in its entirety, usi ng the appropriate starting materials.

[114] Form 1 of SNAC was prepared from the free acid of SNAC by the following procedure, which is also described in Example 12 of Intzernational Publication

No. WO 00/59863.

[115] Into a_ clean 300 gallon reactor was charged 32 1L of ethanol, which was denatured with 0.5% teoluene. While stirring, 109 kg (dry) of tlhe free acid of SNAC was added. The reactor wazs heated to 28° C and maintained at a temperature above 25° C.

A solution of 34 L purifie«d water, USP and 15.78 kg sodium hydlroxide was prepared, cooled to 24° C, and addead to the stirring reactor over 15 minutes, keeping the reaction temperature at 25-35° C. The mixture was stirred for an additional 155 minutes. (116] Into a_n adjacent reactor was charged 321 L o f ethanol, which was denatured with 0.5% toluerme. The reactor was heated to 28° C usiing a circulator. The solution from the first reactor was added to the second reactor over 3CD minutes, keeping the temperature above 25° C. Whe contents were stirred and 418 L of herotane was added. The reaction mixture was cooled to 10° C, centrifuged and then washed with 60 L of heptane.

The product was collected and dried in a Stokes oven at 82° C under 26" EHg vacuum for about 65 hours (over a weekend). 107.5 kg monosodium SNAC (i.e. the m: onosodium salt of N-(8-[2-hydroxybenzoyl]-amino)capryL ic acid) was recovered.

[117] XRPD, DSC, TGA , FTIR, and sorption/desorption spe=ctra for Form I are shown in Figures 1-5, respectively.

Example 2

Preparation £or Form II of SNAC:

[118] Form II of SNAC wvas prepared as follows. The procecdure in

Example 1 was repeated except for the last drying step. The SNAC ethanol ssolvate obtained was then dried in a tumble dryer and agglomerated (formed balls). ~The dryer lacked an internal agitation device. The SNAC was removed from the tumbles dryer, milled with a Comil® milling machine (available from Quadro Engineering Inc. of Waterloo,

Ontario, Canada), and tray dried. The SNAC was stored for at least 3 years zin a double lined polyethylene bag which was placed Ln a stainless steel drum.

[119] XRPD, DSC, TGA, FTIR, and sorption/desorption speactra for Form

II are shown in Figures 6-10, respectively.

Example 3

Preparation for Form III of SNAC.:

[120] Form III was prepar-ed by exposing Form I of SNAC to- a 90% relative humidity environment until Form X could not be detected by XRPD. ~The material was then allowed to dry under a hood unti 1 the moisture content was about 15 % w/w.

(121] XRPD, DSC, TGA, FTIR, and sorpti on/desorption spectra for Form

ITI are shown in Figures 11-15, respectively.

Example 4

Preparation for Form IV of SN AC:

[122] Form IV was prepared by heating Form II for 3 hours in a dry air oven at 170° C. The Form IV prepared had a melting point onset according to DSC of about 198° C, and XRPD, DSC, TGA, FTIR, and sorption/dessorption spectra as shown in

Figures 16-20, :

Example 5

Preparation for Form V of SN_AC:

[123] Form V of SNAC was prepared by sBurring Form I of SNAC in methanol for a week. The resulting precipitate was vacuum filtered and air-dried for an hour. The Form V prepared had a melting point onset according to DSC of about 197° C, and XRPD, DSC, TGA, FTIR, and sorption/desorption spectra as shown in Figures 21-25.

Example 6

Method of Preparation for Form VL of SNAC

[124] Form VI was prepared by slurring Feorm I in ethanol for a week. The resulting precipitate was vacuum filtered and air-dried for an hour. The Form VI prepared had a melting point onset according to DSC of about 197° &C, and an XRPD, DSC, TGA,

FTIR, and sorption/desorption spectra as shown in Figures 226-30.

Example 7

Preparation of Capsules containing Form lor IIL of SNAC and Heparin USP

[125] Capsules (size 1, available from Capsugel of Morris Plains, NJ) containing SMIAC (Form 1 or III) and heparin USP (30,0000 IU) as shown in Table 7 were prepared as follows. SNAC (Form I or III as prepared in Examples 1 and 3) and heparin were screened through mesh #35. The specified amoumt of heparin and SNAC were weighed and transferred to a clean, dry glass 8 oz mortar. A volume of SNAC equivalent to the volume of heparin was added to the mortar and mixed with a pestle for 2 minu_tes.

The remainder of the SNAC was added to the mixture and mixed again for 2 minutes.

Capsules containing the appropriate amount of were fill ed.

Table 7

Quantity per capsule (ang) Quantity per capsule= (mg) '- Assuming Form III of SNAC is a trihydrate, about 1.5.62% (28.39 mg) of Form "Xl is water and thes remaining 84.38% (153.33 mg) is SNACT (on an anhydrous basis).

Administration to Cynos Nvlonkeys

[126] Cynomolgus monkeys (average weight of 4.1 kg for males and 3.0 kg for females) were fasted for at least 24 hours prior to d_osing. 3 SNAC/heparin caps ules were insertecd at the tip of a tubing, and air flushed to discharge the capsules into the= stomach. Fcsod was given back 2 hours after dosing. WVater was available at all timees.

Approsximately 1.3ml of whole blood was collected into citrate~d tubes at pre-dose, and at 10, 208, 30 and 50 minutes, and 1, 1.5, 2, 3, 4 and 6 hours posst dosing. The blood samples were centrifuged for 10 minutes at 2500 RPM and 250 uL of tthe resulting plasma was used with a_ factor Xa assay using an Organon Teknika COAG-A-M ATE MTX/MTX II machi ne. The standard range for the assay was 0-2 IU/mL of heparin.

[127] The results for Forms I and ITI of SNACC with heparin are shown in

Figures 31 and 32, respectively. The results were averaged fomr monkeys by sex and weigh t. In other words, there are data points for 4 monkeys (=x 3.9 kg male, 4.2 kg male, 3.2 kg female, and 2.9 kg female). The results for each form of SNAC at each time point for alR the monkeys were averaged and are shown in Figure 338,

Example 8

Preparation of Capsules containing Form I or III of SN” AC and Heparin USP

[128] Capsules (size 1, available from Capsug el of Morris Plains, NJ) contamning SNAC (Form I or II) and heparin USP (30,000 IU") as shown in Table 7 above were prepared by the procedure described in Example 7.

Administration to Cynos Monkey~s

[129] The procedure described in Example 7 wwvas repeated with 2 male monkeys having an average weight of 5.6 kg and 2 female mownkeys having an average weiglat of 6.9 kg.

[130] The results for Forms I and III of SNACT with heparin are shown in

Figur-es 34 and 35, respectively. The results were averaged fcr monkeys by sex and weight. In other words, there are data points for 4 monkeys Ca 5.7 kg male, 5.6 kg male,

7.6 kg female, and 6.3 kg femzale). The results for each form of SNACT at each time point for all the monkeys were averaged and are shown in Figure 36.

Example 9

Ss [131] The intrimsic dissolution rates for Forms I-IV of SNAC as prepared in

Examples 1-4 were determined as follows.

[132] The intrimsic dissolution rate of pellets of Forms X-IV was determined with a Wood's apparatus. A 300 mg pellet of Form I, II, III, or IV of SNAC was prepared in adie. The surface area of the pellet available to the dissolution med ium was 0.484 cm’.

The pellet was compressed at 1 200-1400 lbs on a Carver press to form discs. The die was then attached to the shaft of a dissolution apparatus. The die was rotated at 50 rpm and then immersed in 900 mL of degassed dissolution medium maintained &at 37° C (pH 6.3).

The dissolution experiments wezre conducted in water and in triplicate. The samples were analyzed by UV-spectroscopy con-line at 297.5 nm. The intrinsic disso lution rates were 1S determined from the initial line=ar portion of the dissolution profile undeer sink conditions.

[133] The resu 1ts are shown in Figures 37 and 38. The calculated dissolution rates for Forms I-I'W are shown in Table 8 below.

Table 8 (mg/min-cm?) or | sews mx | nuses

Example 10 (134] The solub ility of each of Forms I-IV of SNAC in acetonitrile was determined at ambient humidity and 25° C. Acetonitrile was chosen as a solvent since it is one of the few solvents in whicka SNAC is relatively poorly soluble, and the solutions can

S closely approach infinite dilutiomn. The solubility data are shown in Table 9 be low.

Table 9 [ (% standard deviation)

IS NY YET TTR

0 omen ow emeem nT een}

Example 11

[135] The effec of milling on Form I of SNAC was determined as follows.

Milling was performed in a ball -mill. Samples were withdrawn at after 20 hours and analyzed by XRPD.

[136] The XRF®D patterns of the SNAC samples before and after ball milling are substantially the same, as shown in Figure 39.

Example 12

[137] The effecwt of wet granulation on Form I of SNAC was determined as follows. Form I of SNAC was wet granulated manually in a glass mortar witka a pestle as 20% w/w of water was added. The wet granules were analyzed by XRPD.

[138] The XRPD patterns ofS the SNAC samples before and after wet granulat_ion are shown in Figure 40. The samaple after wet granulation exhibits an XRPD pattern substantially the same as that for Form III.

Example 13

[139] The effect of compress-ion on Forms I and III of SNAC was evaluated as follows. Approximately 300 mg of each s-ample was compacted on a Carver press with 4500 Ib force and 1 minute dwell time. The compression cycle was repeated 20 t#mes.

The crysstal form of the SNAC in the compossition was analyzed by XRPD.

[140] The results for Forms 1and III are shown in Figures 41 ancl 42, respectively. As shown by these figure, the crystal form in both samples did not substant ially change.

Exarmple 14

Preparation of AAmorphous SNAC

[141] Amorphous form was gprepared by drying Form III in a vacwum oven at 25° C= and 0.3 in. of Hg for 4 days. The dri_ed material was a mixture of amorphous form and appmroximately 10% of initial Form III of SNAC. Longer drying and higher vacuum may res ult in substantially pure and pure ameorphous form.

[142] XRPD, DSC, TGA, F TIR, and sorption/desorption spectra for the amorpheous SNAC containing approximately 10% of Form III are shown in Figurees 43-47, respecti—vely.

[143] All patents, applications, articles, publications, and test methods mentione=d above are hereby incorporated by reference.

Claims (1)

1. We claim:

   l. Monosodium N-[8-(2-hydr-oxybenzoyl)amino]capr-ylate 1/3 hydrate.

   2. A crystalline polymorph of monosodium N-[8-(2- hydroxybenzoyl)amino]caprylate hydrate exhibit ing an X-ray powder dif~fraction pattern substantially as shown in Figure 6.

   3. A crystalline polymorph of monosodium N-[8-(2-tmydroxybenzoyl)- amino]caprylate hydrate exhibiting an X-ray powder diffraction pattern Inaving peaks in degrees 260 +0.2 20 at 3.29, 11.96, and 17.76.

   4. The crystalline polymorph of claim 3, wherein the crystalline polymorph has a melting point onset as determin ed by differential scanning calorimetry at about 199° C.

   5. Monosodium N-[8-(2-hydr oxybenzoyl)amino]caprye late trihydrate.

   6. A crystalline polymorph off monosodium N-[8-(2- hydroxybenzoyl)amino]caprylate hydrate exhibiting an X-ray powder dif=fraction pattern substantially as shown in Figure 11.

   7. A crystalline polymorph ofS monosodium N-[8-(2- hydroxybenzoyl)amino]caprylate hydrate exhibiting an X-ray powder difzfraction pattern having peaks in degrees 20 +0.2 26 at 6.69, W3.58, and 16.80. 43 AMENDED SHEET

   8. Thhe crystalline polymorph of clainmn 7, wherein the crystalline polymorph has a melting point onset as determined by dm fferential scanning calorimetry at about 198° C.

   9. A crystalline polymorph of anhydr—ous monosodium N-[8-(=2- S hydroxybenzoyl)amino]ecaprylate exhibiting an X-ray powder diffraction pattern substantially as shown im Figure 16.

   10. A crystalline polymorph of anhydr—ous monosodium N-[8-(2- hydroxybenzoyl)amino]czaprylate exhibiting an X-ray powder diffraction pattern faving peaks in degrees 26 +00.2 26 at 8.61, 17.04, and 23.228.

   11. The crystalline polymorph of claim 10, wherein the crystal line polymorph has a melting point onset as determined by differential scanning calormmetry at about 198° C.

   12. A methanol-water co-solvate of monosodium N-[8-(2- hydroxybenzoyl)amino]caprylate.

   13. A methanol-water co-solvate of monosodium N-[8-(2- hydroxybenzoyl)amino)caprylate wherein the ratio of me=thanol to water to monosodium N- [8-(2-hydroxybenzoyl)armino]caprylate is approximately @0.8:2:1. 44 AMENDED SHEET

   14. A crystalline polymorph of” a methanol-water co-solva_te of monosodium N-[8-(2-hydroxybenzoyl)amino]capmrylate exhibiting an X-ray powder diffraction pattern substantially as shown in Figume 21.

   15. A crystalline polymorph of” a methanol-water co-solva_te of moonosodium N-[8-(2-hydroxybenzoyl)amino]capmrylate exhibiting an X-ray powder dliffraction pattern having peaks in degrees 26 4=0.2 26 at 6.59, 9.96, 10 86, 13.87,

   1.7.29, and 19.92.

   16. The crystalline polymorph of claim 15, wherein the cmrystalline polymorph has a melting point onset as determined by differential scanning calorimetry at about 197° C.

   17. An ethanol-water co-solvatee of monosodium N-[8-(2- Ia ydroxybenzoyl)amino]caprylate.

   18. An ethanol-water co-solvat-e of monosodium N-[8-(2- hydroxybenzoyl)amino]caprylate wherein the ratio of ethanol to water to mcnosodium N-[8- ( 2-hydroxybenzoyl)amino]caprylate is approximautely 0.6:2:1.

   19. A crystalline polymorph of” an ethanol-water co-solvaste of rnonosodium N-[8-(2-hydroxybenzoyl)amino]cap-rylate exhibiting an X-ray gpowder cliffraction pattern substantially as shown in Figure 26. 45 AMENIDED SHEET

   20. A crystalline polymorph of an e=thanol-water co-solvate of monosodiurm N-[8-(2-hydroxybenzoyl)amino]caprylatee exhibiting an X-ray powder diffraction goattern having peaks in degrees 26 +0.2 26 at 9.60, 10.43, 12.68, and

   16.58.

   21. The crystalline polymorph of cl aim 15, wherein the crystalline polymorph has a melting point onset as determined by~ differential scanning calorimetry at about 197° «C.

   22. Amorphous monosodium N-[8-«2-hydroxybenzoyl)amino]caprylate.

   23. A pharmaceutical composition comprising (A) (i) the crystalline polymorph of any of claims 1-21 or (ii) amorphous monosodium N-[8-(2- hydroxybemzoyl)amino]caprylate, and (B) an active agent.

   24. The pharmaceutical compositiom of claim 23, wherein the active agent is heparin.

   25. The pharmaceutical compositiom of claim 24, wherein the active agent is low molecular weight heparin.

   26. Use of the pharmaceutical composition of claim 23 in the manufacturee of a medicament for administering the a.ctive agent to an animal in need thereof . 46 AMENDED SHEET

   28. A method of preparing Form I of SNACT comprising the step of heating Form III, “V, or VI of SNAC or a mixture thereof to aat least 50° C to yieldz Form I of SNAC for a tine sufficient to form Form I of SNAC.,

   29. The method of claim 28, wherein the SENAC is heated to fromm about 50 to about 110° CT for a time sufficient to form Form I of SNIAC.

   30. A method of preparing Form I of SNA®C comprising the stejo of heating amorphous SNAC at from about 30 to about 90° C foor a time sufficient to form Form I of SNAC.

   31. The method of claim 30, wherein the a_morphous SNAC is Ineated at - from about 40 to about 80° C.

   32 . A method of preparing Form I of SNA_C comprising the step of lyophilizing any form of SNAC other than Form I to yield Feorm I.

   33 . The method of claim 32, wherein the rmnethod comprises lycaphilizing one or more of F orms II-VI of SNAC and/or amorphous SN” AC to yield Form I.

   34-. A method of preparing Form II of SN.AC comprising the stzep of drying a solvate eof SNAC without agitation and exposing thes dried SNAC to moi sture for a sufficient time to yield Form II of SNAC.

   35. The method of claim 34, wherein the solvate is an ethanol solvate or a methanol -solvate.

   36. A method of preparing Form III of SNAC comprising the step of exposing Form I, II, IV, V, or VI of SNAC or amorphous SNAC or a mixture thereof to an environrment having a relative humidity of 75% or greater for a sufficient time to yield Form III.

   37. A method of preparing Form IIT of SNAC comprising the step of wet granulatings Form I of SNAC for a sufficient time to yield Form III.

   38. A method of preparing Form IIK of SNAC comprising the step of exposing F=orm V or VI of SNAC or a mixture thereo f to an environment having a relative humidity o=f 30% or greater for a sufficient time to yield Form III.

   39. A method of preparing Form IIT of SNAC comprising the step of exposing FForm VI of SNAC to an environment havin g a relative humidity of 10% or greater for a sufficient time to yield Form III.

   40. A method of preparing Form IKI of SNAC comprising the step of exposing amorphous SNAC to moisture for a sufficient time to yield Form III.

   41. A method of preparing Form ITI of SNAC comprising the step of crystallizi ng SNAC from water.

   42. A method of preparing Form IV of SNAC compris: ing the step of heating Form I, II, IlI, V, or VI of SNACT or a mixture thereof to a temperature between about 110° C and the melting point of SN AC for a sufficient time to yielad Form IV. 43, The method of claimm 42, wherein the Form II of STNAC is heated to between about 150° C and the melting po=int of SNAC for a sufficient tine to yield Form

   Iv.

   44. A method of preparing Form V of SNAC comprising the step of crystallizing SNAC from a methanol soltation at a relative humidity of at least about 30%.

   45. The method of clai m 44, wherein the methanol soRution is substantially free of water.

   46. A method of prepa_ring Form V of SNAC compris- ing the step of equilibration of Forms I-IV or VI of SN~AC with methanol.

   47. The method of clamm 46, wherein the equilibratior is performed in the absence of water.

   48. A method of preparing Form V of SNAC comprising the step of slurring any of Forms I-IV or VI or a mixture thereof in methanol at a relative humidity of at least 30%, and maintaining the slurrie=d mixture at ambient temperatumres for a sufficient time to form Form V.

   49. A method of preparing Form VI of SNAC comprising the step eof c_xystallizing SNAC from an ethanol solution at a relative humidity of at least about 300%.

   50. The method of claim 4-9, wherein the ethanol solution is substaratially fmee of water. S S51. A method of preparingg Form VI of SNAC comprising the stepss of preparing a saturated solution of SNAC in ethanol at a relative humidity of at least about 30% and cooling the resulting solution to roeom temperature or lower.

   52. The method of claim S51, wherein the method is performed in the absence of water.

   53. A method of preparingz Form VI of SNAC comprising the step of slurring any of Forms I-IV in ethanol at a relative humidity of at least about 30%.

   54. A pharmaceutical composition comprising a milled mixture of . Form I of SNAC and at least one active agent or ph_armaceutically acceptable additive.

   55. A pharmaceutical conmposition comprising a directly compresse=d mmixture of Form I of SNAC and at least one active agent or pharmaceutically accept=able additive,

   56. A pharmaceutical composition. comprising a directly compressed mixture of Form III of SNAC and at least one actives agent or pharmaceutically acceptab le additive.

   57. A method of preparing amorphous SNAC comprising the step of dehydrating Form III, V, or VI of SNAC for a suffi cient time to form amorphous SNAC..

   58. The method of claim 57, wherein Form III, V, or VI of SNAC is dehydrated ira a vacuum.

   59. The method of claim 57, whemrein Form III is dehydrated to form amorphous S NAC.

   60. A method of preparing Forms 1 to VI of SNAC substantially as herein exemplified with reference to Examples 1 to 6 respectively.

   61. A pharmaceutical compositiora comprising Form I or Form III of SNAC substantially as herein exemplified with refemrence to Examples 7 or 8. 51 AMENDED SHEET