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Novel crystalline forms of an nrtti compound

A crystallization and form technology, applied in the fields of carbohydrate active ingredients, organic chemistry, sugar derivatives, etc.

Pending Publication Date: 2021-07-30
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when utilizing the known monohydrate crystalline form of EFdA, in situ recrystallization occurs during the hot melt extrusion (HME) formulation process, which results in the conversion of the monohydrate crystalline form of EFdA into multiple Thermodynamically unfavorable mixture of anhydrous phase

Method used

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  • Novel crystalline forms of an nrtti compound
  • Novel crystalline forms of an nrtti compound
  • Novel crystalline forms of an nrtti compound

Examples

Experimental program
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Effect test

Embodiment 1

[0198] The Gibbs free energy (ΔG) of a phase is a fundamental thermodynamic parameter that determines the relative stability of a polymorph at a given temperature. The solubility of a particular polymorph is related to ΔG by the equation ΔG = -RTln(solubility). The polymorph with the lowest solubility is considered the thermodynamically stable phase at a given temperature. Table 6 lists the measured solubility of Forms 1, 2 and 4 of EFdA in acetonitrile between 25.0 and 65.0°C. The data clearly demonstrate that the most thermodynamically stable phase of EFdA is Form 4 and that Form 2 is the least stable phase in the measured temperature range. Relatively low ΔΔG values ​​for conversion of Form 1 to Form 4 (i.e., small energy gap between Form 1 and Form 4; 0.21–0.35 kJ / mol), fast crystallization kinetics compared to Form 1 and Form 4 The combination of polymorphism and polymorphism results in the difficulty of isolating form 4 using conventional polymorphic screening methods....

Embodiment 2

[0203] Example 2: Monohydrate crystalline form MH of EFdA

[0204] Form MH of EFdA can be obtained in suitable starting amounts by the synthetic method described in US Patent No. 7,339,053.

[0205] As will be appreciated by those skilled in the art, the use of seed crystals in the preparation of Form 1 and Form 4 as described in Examples 4 and 6 is not initially required, but after making initial quantities of crystalline Form 1 and Form 4 respectively for optimal preparation.

Embodiment 3

[0206] Example 3: Anhydrous crystalline form 1 of EFdA

[0207] EFdA Form 1 was prepared by adding 1.92 grams of EFdA solid and 16.0 grams of methanol (MeOH) to a clean reactor and heating to 65 °C while stirring. The mixture was cooled to 40°C over 30 minutes, to 20°C over 1 hour, then stirred at 20°C for ~14 hours. Filter the slurry and pass through N at ambient temperature 2 The filter cake was dried by passing the filter cake for 2 hours. 1.59 g of EFdA Form 1 was collected in ~88% isolated yield.

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Abstract

The present disclosure provides novel anhydrate crystalline Forms 1 and 4 of 4'- Ethynyl-2-fluoro-2'-deoxyadenosine and pharmaceutical compositions thereof, each of which may be useful for the inhibition of HIV reverse transcriptase, the treatment or prophylaxis of HIV infection and / or the treatment, prophylaxis and / or delay in the onset or progression of AIDS or ARC.

Description

[0001] Background of the invention [0002] Human immunodeficiency virus (HIV-1) infection is a serious condition that, if left untreated, eventually destroys the host's immune system leading to acquired immunodeficiency syndrome (AIDS) and premature death. Despite advances in antiretroviral therapy (ART), HIV remains a global epidemic and a global public health priority. In 2012, an estimated 35 million people worldwide were living with HIV (Global Report: UNAIDS report on the global AIDS epidemic2013. UNAIDS / JC2502 / 1 / E). In the United States, an estimated 1.2 million people are living with HIV and approximately 50,000 are newly infected each year. HIV seropositive individuals are initially asymptomatic but often develop AIDS-related syndrome (ARC) followed by AIDS. More than 650,000 people have died of AIDS in the United States and more than 14,000 new deaths are reported each year. Treatment can help HIV patients live longer and healthier lives, but currently only 30 per...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/70C07H19/16C07H19/173
CPCC07H19/16C07H19/173A61K31/7076A61P31/14C07B2200/13
Inventor D·斯科姆斯基苏永超徐炜M·库布罗维奇
Owner MERCK SHARP & DOHME BV
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