MXPA00006747A - Bisulfate salt of hiv protease inhibitor - Google Patents
Bisulfate salt of hiv protease inhibitorInfo
- Publication number
- MXPA00006747A MXPA00006747A MXPA/A/2000/006747A MXPA00006747A MXPA00006747A MX PA00006747 A MXPA00006747 A MX PA00006747A MX PA00006747 A MXPA00006747 A MX PA00006747A MX PA00006747 A MXPA00006747 A MX PA00006747A
- Authority
- MX
- Mexico
- Prior art keywords
- salt
- free base
- bisulfate salt
- solubility
- bisulfate
- Prior art date
Links
- QAOWNCQODCNURD-UHFFFAOYSA-M bisulphate group Chemical class S([O-])(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 title abstract description 34
- 239000004030 hiv protease inhibitor Substances 0.000 title abstract description 6
- 150000003839 salts Chemical class 0.000 claims description 23
- 239000011780 sodium chloride Substances 0.000 claims description 20
- -1 salt bisulfate Chemical class 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims 2
- 229960001948 caffeine Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000012458 free base Substances 0.000 abstract description 30
- 150000001875 compounds Chemical class 0.000 abstract description 17
- 230000035536 Oral bioavailability Effects 0.000 abstract description 9
- 230000036220 oral bioavailability Effects 0.000 abstract description 9
- 238000004090 dissolution Methods 0.000 abstract description 2
- 229910001868 water Inorganic materials 0.000 description 23
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000000725 suspension Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000007790 solid phase Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 239000002253 acid Substances 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- 150000003840 hydrochlorides Chemical class 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate Chemical class CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000006011 modification reaction Methods 0.000 description 4
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 239000006186 oral dosage form Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000007707 calorimetry Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000005712 crystallization Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 1
- 230000036912 Bioavailability Effects 0.000 description 1
- 229960000913 Crospovidone Drugs 0.000 description 1
- 241000083551 Ena Species 0.000 description 1
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229920002892 amber Polymers 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- SPCNPOWOBZQWJK-UHFFFAOYSA-N dimethoxy-(2-propan-2-ylsulfanylethylsulfanyl)-sulfanylidene-$l^{5}-phosphane Chemical compound COP(=S)(OC)SCCSC(C)C SPCNPOWOBZQWJK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- UMYZHWLYICNGRQ-UHFFFAOYSA-N ethanol;heptane Chemical compound CCO.CCCCCCC UMYZHWLYICNGRQ-UHFFFAOYSA-N 0.000 description 1
- XTLNYNMNUCLWEZ-UHFFFAOYSA-N ethanol;propan-2-one Chemical compound CCO.CC(C)=O XTLNYNMNUCLWEZ-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-M hydrosulfide Chemical class [SH-] RWSOTUBLDIXVET-UHFFFAOYSA-M 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- LRPCLTPZMUIPFK-UHFFFAOYSA-L methane;sulfate Chemical compound C.[O-]S([O-])(=O)=O LRPCLTPZMUIPFK-UHFFFAOYSA-L 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Abstract
The present invention provides the crystalline bisulfate salt of formula (II) which is found to have unexpectedly high solubility/dissolution rate and oral bioavailability relative to the free base form of this azapeptide HIV protease inhibitor compound.
Description
BISULFATE SALT OF THE HIV PROTEASE INHIBITOR BACKGROUND OF THE INVENTION
1. Field of Invention The present invention provides the novel crystalline bisulfate salt of the azapeptide HIV protease inhibitor of formula
which exhibits unexpectedly superior aqueous solubility / solubility behavior compared to other salts; and a significantly improved oral bioavailability with animals compared to free base. The bisulfate salt is thus useful for pharmaceutical dosage forms of the protease inhibitor
REF .: 120222 indicated above, particularly the oral dosage forms.
2. Background of the technique. The PCT patent application WO97 / 40029 published discloses a series of azapeptide HIV protease inhibitors reported to have a high degree of inhibitory activity against the HIV virus. One of the agents included in the field of patent WO 97/40029 is the compound having the structural formula:
and the chemical name dimethyl ester of acid [SSOR *, 8'R *, 9'R *, 12R *)] -3,12-bis (1,1-dimethylethyl) -8-hydroxy-4,11-dioxo- 9- (phenylmethyl) -6- [[4- (2-pyridinyl) -phenylmethyl] -2, 5, 6, 10, 13-pentaazatetradecanedioic, and is under evaluation as a possible second generation of the HIV protease inhibitor.
WO 97/40029 discloses the free base form of the azapeptide derivatives such as compound I and also various pharmaceutically acceptable acid addition salts. While various organic and inorganic acids are mentioned as possible salts forming agents, including sulfuric acid, there is no mention of the bisulfate salt in particular which is the subject of the present application.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides the bisulfate salt of the aforementioned compound I having the following structural formula:
p
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the pH - solubility profile of the "aqueous suspension.
Figure 2 shows the physical stability of the bisulfate salt. The line l ena represents the material to which you have not been subjected to an effort. The dotted line represents the material that has been subjected to an effort at 40 ° C / 75% RH for 9 months.
Figure 3 shows the physical stability of the hydrochloride salt. The full line represents the material that has not been submitted to an effort. The dotted line represents the material subjected to an effort at 40 ° C / 75% RH for two weeks.
Figure 4 shows the physical stability of the methane sulfonate salt. The full line represents the material without being subjected to an effort. The dotted line represents the material subjected to an effort at 40 ° C / 75% RH for two weeks.
Figure 5 shows' the physical stability of the sulfate salt. The full line represents the material without being subjected to an effort. The dotted line represents the material that has been subjected to an effort at 40 ° C / 75% RH for two weeks.
DETAILED DESCRIPTION OF THE INVENTION
Compound I as described above is an organic weak base with a solubility of less than 1 μg / ml at 24 ± 3 ° C. The form of the crystalline free base as a suspension in water or in oil has a poor oral bioavailability in animals, probably because it has a low solubility in these vehicles.
For the development of pharmaceutical formulations, particularly oral dosage forms, the active ingredient must have sufficient oral bioavailability. Since the free base form of compound I did not possess such bioavailability, the acid addition salts were explored by the present inventors. A number of commonly used acid addition salts such as the hydrochloride, benzenesulfonate, methanesulfonate, p-toluenesulfonate, phosphate, nitrate, 1,2-ethanedisulfonate, isothioate and sulfate are further evaluated for the bisulfate salt of the present invention. All these salts in their crystalline form exhibit a very low aqueous solubility (1-3 mg / ml or less at 24 ± 3 ° C) than the bisulfate which has a solubility under the same conditions of about 4-5 mg / ml.
The transformation of the solid state is then observed when other acid addition salts mentioned above are suspended in water, probably due to their dissociation to form the free base. In most cases, this transformation is accompanied by gel formation. Unlike other salts mentioned above, the extra proton of the bisulfate salt prevents the conversion of the free base which, as mentioned above, is very insoluble in water and has poor oral bioavailability. The behavior of the unusual solubility of the bisulfate salt in water is further elaborated in the following.
In general, the conversion of the salts to the non-ionized form or vice versa can be explained on the basis of the theory of solubility-pH. The solubility of the free base in water is determined as a function of the pH at 24 ± 3 ° C and which is shown below. The pH at which the compound exhibits the highest solubility is referred to as a pH max and is found to be about 1.2. It has been reported in the literature that a pH > pHmax of a weakly basic organic compound, the equilibrium of the solid phase is an aqueous suspension of the compound is the free base. At a pH < pHmax the balance of the solid phase is converted to the corresponding salt form. The term "equilibrium of the solid phase" refers to an excess or non-dissolved solid in a suspension of the compound in water after sufficient equilibrium time. When a salt of a base of bCl is equilibrated with water in an amount that exceeds its solubility limit (ie a suspension of the salt in water), the resulting pH of the suspension may fall either on the pHmax side depending on the strength of the acid between two factors. When the resulting pH is greater than the pHmax the suspended solid is converted to the free base see Figure 1.
Studies conducted with methane sulfate and hydrochloride salts, in particular, of the free base, confirm the general findings described above reported in the literature. Quantities in excess of the solubility of these salts are equilibrated in water 24 ± 3 ° C for at least 24 hours. The pH of the suspensions after equilibrium is 2.1 ± 0.1 which is greater than the pHmax. Unresolved bolides from these suspensions are isolated, air dried, and characterized. By thermal and elemental analysis the undissolved solids of those suspensions are identified as the free base. This behavior is expected based on the pH-solubility profile shown in the graph of Figure 1 and the studies reported in the literature.
When an excess amount of the bisulfate salt is balanced in water, a modification in the solid phase occurs in equilibrium with the solution. However, the solid phase not dissolved after equilibrium is not the free base, although the pH (1.9 ± 0.2) of the suspension is greater than the pHmax and comparable to the pH of the methane sulphonate and hydrochloride salt suspensions described previously. The solid phase after at least 24 hours of equilibrium is identified by elemental analysis as a hydrated form of salt 2: 1 of the free base form and the sulfuric acid (referred to as the sulfate salt).
This behavior of the bisulfate salt is unexpected based on the pH-solubility theory.
When an excess amount of the sulfate salt, in turn, is balanced with water, a modification in the solid phase occurs in equilibrium with the solution. The undissolved solids of this suspension are isolated, air dried, and characterized. A thermal and elemental analysis of this undissolved solid phase is similar to that of the free base, although the conversion of the sulfate salt to the free base is not definitive like that of sulfonate methane and hydrochloride salts. From a pharmaceutical point of view, the propensity of the salts to convert the free base into an aqueous environment is not advisable due to the low oral bioavailability of free base. In this way, the bisulfate salt due to its unique solubility behavior in water offers unexpected superiority.
The solubility behavior of the bisulfate salt in water is also unexpected considering the interaction of the free base of compound I and sulfuric acid in water. For example, the free base exhibits a solubility of less than 1 mg / ml in water at a pH of ~ 1.8 adjusted with sulfuric acid, compared to the solubility of 4-5 mg / ml of the bisulfate salt in water at pH conditions comparable. Based on the theory of pH-solubility it is expected that the free base and the salt exhibit a solubility similar to a given pH.
The improved solubility / dissolution behavior of bisulfate contributes to improved oral bioavailability in animals relative to the free base. The absolute oral bioavailability of the bisulfate salt was found to be approximately 20% in dogs when administered in an unformulated solid form placed in a gelatin capsule. In comparison, the crystalline free base has a minimal oral bioavailability in dogs.
In addition for optimum solubility, satisfactory physical stability in the solid state is another desirable property of pharmaceutical salt forms. Thermal physical stability indicates the ability of the salt form to retain the crystalline structure (including crystallization solvents, perhaps) under storage / stress conditions. Significant changes in the physical nature of the salt form as indicated by thermal methods such as differential analysis calorimetry are undesirable. The bisulfate salt exhibits excellent physical stability in the solid state when stored at 40 ° C / 75% relative humidity (RH) for 9 months as shown in Table 1 below. The differential analysis calorimetry reveals that there are no significant changes in the thermal behavior of the sample which is subjected to an effort of the bisulfonate salt compared to the sample that has not been subjected to an effort (stored at 2-8 ° C in a closed container). Methane sulfonate, hydrochloride, and sulfate salts, on the other hand, show significant changes in their thermal behavior when stored at 40 ° C / 75% RH for at least two weeks as shown in the graph of Figure 2, 3 and 4. While differences in the physical stability of salt forms is not unusual, the propensity of a particular salt to form solvates (or crystal modifications) and the ability to retain the crystallization solvent (the physical stability of crystal modifications) under storage / stress conditions can not be predicted a priori.
The bisulfate salt can be prepared by fuming a free base solution of compound I with sulfuric acid in solvents such as acetonitrile, isopropanol, ethanol, or acetone and then the bisulfate salt is thus produced.
- Due to its high availability as well as its good crystallinity and stability, the bisulfate salt is very useful in the preparation of oral dosage forms of compound I. The examples given below illustrate the preparation of representative oral formulations.
The bisulfate salt, and formulations thereof, are used as described in WO 97/40029 for the treatment of diseases caused by viruses, specifically retroviruses such as the HIV virus.
DESCRIPTION OF THE SPECIFIC MODALITIES
Example 1
Preparation of the bisulfate salt of ethanol
To a 500 ml three neck round bottom flask equipped with an overhead stirrer and a dropping funnel were added with stirring 15.013 g (0.0213 moles) of free base of compound I and 113 ml of grade 200 ethanol. To this suspension, 1.28 ml of concentrated sulfuric acid is added drop by drop for 90 seconds. After the addition of the sulfuric acid, a clear amber colored solution is obtained. The solution is subjected to a refining filtration using Whatman No. 1 filter paper and washed with 5 ml of grade 200 ethanol. add 58 ml of heptane and 37.5 mg (0.25% by weight) of seed crystals of the compound of formula II followed by 55 ml of additional heptane. The resulting mixture is stirred for 6 hours at 300 rpm. The resulting glass slurry is filtered and washed with 50 ml of a (1: 1) ethanol / heptane solution and dried under vacuum at 60 ° C overnight to yield 15.11 g of the desired crystalline bisulfate salt (88.4 mol% of yield) having the formula II above. Characterization properties of the bisulfate salt Analysis calculated for: C38H52N60 «1.0 H2S0: C56.84; H, 6.78; N, 10.37; S, 3.99. Found: C, 56.72; H, 6.65; N, 10.41; S, 3.83. p.f. 195.0 ° H20 = 0.28% (KF).
Example 2
Preparation of the bisulfate salt from acetone.
5M H2SO4 (8.52 ml, 42.6 mM) is added dropwise to a suspension of the free base of the compound of formula I
(30.0 g, 42.6 mM) in acetone (213 mL) and mechanically stirred in an oil bath at 50 ° C. A clear solution is obtained almost immediately. The solution is seeded with crystals of the free base of the compound of formula II. After two minutes, a formed precipitate becomes a paste. The mixture is stirred at 50 ° C for one hour at 25 ° C for 30 minutes and at 0 ° C for 2 hours.
The solid is filtered and the first filtrate is used to transfer the remaining material in a flask for the filtration in the funnel. The product is washed with acetone, then with heptane, and dried under vacuum overnight to yield 31.48 g (92% corrected yield) of the bisulfate salt of formula II, m.p. 198-199 ° C dec.
Analysis calculated for: C38H52N6? 7 * 1 .0 H2SO4 »0.2 H20: C, 56.59; H, 6.80; N, 10.42; S, 3.98; H2O, 0.45. Found: C, 56.66; H, 6.78; N, 10.50; S, 4.20; H20 0.45 (KF).
Example 3
Preparation of the bisulfate salt from isopropanol.
Aqueous sulfuric acid (5.0 M, 0.20 ml, 1 mM) is added to a solution of the free base of the compound of formula I (0.704 g, 1.00 mM) in isopropanol (4.0 ml) cooled in an ice bath. The ice bath is removed and the mixture is stirred at room temperature. The suspension has dissolved after 15 minutes. The solution is seeded with crystals and prepared as in Examples 1 or 2 described above and stirred for 5 hours. The solid is filtered and the filtrate is used to transfer the solid from the flask to the funnel. The product is washed with heptane and dried under vacuum to provide 0.752 g of the crystalline bisulfate salt of formula II, 90% yield, m.p. 160-190 ° C, dec.
Analysis calculated for: C38H52N6? 7 «l .0 H2.S0» 2.0 H20; C, 54.40; H, 6.97; N, 10.02; S, 3.82; H20, 4.29. Found: C, 54.25; H, 6.73; N, 10.02; S, 3.67; H20, 4.53 (KF). The crystals obtained from isopropanol show a powder X-ray diffraction pattern different from the crystals obtained from acetonitrile, ethanol-heptane or acetone. These are not referred to as Type II crystals. Type I crystals appear to be an anhydrous / desolvated crystalline material while Type II crystals are a crystalline, hygroscopic, and hydrated form.
Example 4
Preparation of capsule formulations of the bisulfate salt.
A. Capsules (50 and 200 mg equivalent free base).
The capsules are provided for oral administration where the capsule is in a hard, opaque, gray-colored, # 0-size gelatin capsule containing the bisulfate salt of formula II formulated as a wet granulation with lactose, crospovidone and magnesium stearate.
B. Capsules (100 mg of free base equivalent)
The capsules are provided for oral administration where the capsule is a gray, opaque, hard, gelatin capsule of size # 0 and containing the bisulfide salt of formula II suspended in Gelucire 44/14. Gelucire 44/14 is a saturated polyglycolized glyceride consisting of mono-, di- and triglycerides and esters of mono- and di-fatty acids of polyethylene glycol. The capsules are prepared by melting Gelucire 44/14 at 45-70 ° C followed by the addition of the bisulfate salt with stirring. The molten mixture is filled into gelatin capsules and allowed to cool and solidify.
It is noted that in relation to this date, the best method known to the applicant, to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:
Claims (2)
1 . The salt bisulfate characterized because it has the formula 0CH3
2 . A pharmaceutically acceptable caffeine park salt dosage form according to claim 1 and a pharmaceutically acceptable carrier.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60/071,968 | 1998-01-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00006747A true MXPA00006747A (en) | 2001-06-26 |
Family
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