Guanine derivative

Details Guanine derivative Guanine derivative

1997-09-22

2000-08-22

Travers, Russell

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544267, 544276, 544277, 544229, 544244, A01N 4390, C07F 502, C07F 902, C07D47300

Patent

active

061073024

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a specific crystalline form of the antiviral compound valaciclovir hydrochloride, and to a process for producing it.
The compound 9-[(2-hydroxyethoxy)methyl]guanine, otherwise known as acyclovir possesses potent antiviral activity and is widely used in the treatment and prophylaxis of viral infections in humans, particularly infections caused by the herpes group of viruses (see, for example, Schaeffer et al, Nature, 272, 583-585 (1978), UK patent no. 1,523,865 and U.S. Pat. No. 4,199,574). However, acyclovir is poorly absorbed from the gastrointestinal tract upon oral administration and this low bioavailability means that multiple high doses of oral drug may need to be administered, especially for the treatment of less sensitive viruses or infections in order to achieve and maintain effective anti-viral levels in the plasma.
The L-valine ester of acyclovir, namely (2-[2-amino-1,6-dihydro-6-oxo-purin-9-yl)methoxylethyl L-valinate, (otherwise known as valaciclovir) has been shown to possess much improved bioavailability whilst retaining the anti-viral properties of acyclovir. A preferred form of this compound is its hydrochloride salt which is otherwise known as valaciclovir hydrochloride. The L-valinate ester of acyclovir and its salts including the hydrochloride salt are disclosed in U.S. Pat. No. 4,957,924 (see particularly example IB), European Pat. No. 0308,065 (see particularly example IB) and Beauchamp et al, Antiviral Chemistry and Chemotherapy, 3(3), 157-164 (1992) (see particularly page 162 column 1).
We have now found that valaciclovir hydrochloride can exist in various forms, and moreover we have discovered a form of valaciclovir hydrochloride which is anhydrous and crystalline and which surprisingly has particularly good pharmaceutical properties. It is particularly stable and essentially non-hygroscopic. Batches of this crystalline form can be consistently made to a high crystal form purity i.e. where the proportion of other amorphous and crystalline forms of valaciclovir hydrochloride is limited. Furthermore this anhydrous crystalline form has good storage properties and can be readily formulated into pharmaceutical compositions such as tablets and capsules.
Accordingly in a first aspect of the invention there is provided valaciclovir hydrochloride in anhydrous crystalline form including the following d spacing pattern (in Angstroms): 5.37.+-.0.02, 5.23.+-.0.02, 4.89.+-.0.02, 4.42.+-.0.02, 4.06.+-.0.02, 3.71.+-.0.02, 3.39.+-.0.02, 3.32.+-.0.02, 2.91.+-.0.02, 2.77.+-., 0.02.
Hereinafter by "anhydrous crystalline form" according to the invention, we mean a crystalline form having substantially the same X-ray powder diffraction pattern as shown in FIGS. 1 to 3, or having substantially the same d spacing pattern as defined above.
Any particular crystalline form of a molecule will have its own unique d spacing pattern which can be determined from its powder X-ray diffraction pattern using the Bragg equation
It will be appreciated that the measured d spacings can vary slightly e.g. depending on the degree to which the powder sample is packed.
The invention relates to the anhydrous crystalline form both in pure form and in admixture with other forms of valaciclovir hydrochloride such as hydrated crystalline forms. For example in any batch containing the anhydrous crystalline valaciclovir hydrochloride, there may also be hydrated crystalline forms of the compound. Preferably the crystal form purity in any drug batch of valaciclovir hydrochloride is at least 70% w/w, more preferably at least 80% w/w, more preferably still at least 90% w/w, and most preferably at least 95% of anhydrous crystalline valaciclovir hydrochloride (as defined above).
In an alternative method of determining crystal form purity, since the anhydrous crystalline form of valaciclovir hydrochloride is essentially free of water of hydration, the proportion of hydrate forms of valaciclovir hydrochloride in any batch of the compound can be measured by the overall water of hydration content of each batch

REFERENCES:
Antiviral Chemistry & Chemotherapy, vol. 3, No. 3. 1992, pp. 157-164 XP002000503 Beauchamp et al p. 162 left hand column.
Antiviral Chemistry & Chemotherapy (1992) 3(3), 157-164 Beauchamp et al "Amino acid ester prodrugs of acyclovir".

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