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Crystalline Composition Containing 1-{[(α-isobutanoyloxyethoxy)carbonyl]- aminomethyl}-1-cyclohexane acetic acid and Sugar-Excipient

IP.com Disclosure Number: IPCOM000191128D
Publication Date: 2009-Dec-17
Document File: 3 page(s) / 100K

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The IP.com Prior Art Database

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Crystalline Composition Containing 1-{[(α-isobutanoyloxyethoxy)carbonyl]- aminomethyl}-1-cyclohexane acetic acid and Sugar-Excipient

    1-(aminomethyl)cyclohexaneacetic acid is known as GBP. GBP has the molecular formula C9 H17NO2, a molecular weight of 171.24gr/mol and the following chemical structure:

    GBP is a white to off-white crystalline solid with a pKa1 of 3.7 and a pKa2 of 10.7. GBP is used in the treatment of cerebral diseases such as epilepsy.

    1-{[(α-isobutanoyloxyethoxy)carbonyl]-aminomethyl}-1-cyclohexane acetic acid, known as GBPE, is a transported prodrug of GBP. GBPE has the molecular formula C16H27NO6, a molecular weight of 329.39gr/mol and the following chemical structure:

    GBPE is designed to improve some of the bioavailability limitations that are known in GBP. GBPE is designed to be recognized by high-capacity transport proteins expressed all along the intestinal tract, making it suitable for sustained-release formulation for colonic absorption. After absorption, GBPE is rapidly converted to GBP.

    GBPE known in the art is either in an oily form that is not easy to handle in pharmaceutical industry or crystallized from its oily form by a process that is not easily carried out. Here is provided a crystalline composition containing GBPE and sugar excipient such as lactose monohydrate, mannitol and sorbitol, as well as a process for its preparation. The preparation of it is done directly from its oily form or from the reaction mixture after the final step of GBPE synthesis is taken, and therefore prevents the need of the complicated crystallization of the GBPE from its oily form.

    As used herein, the term "room temperature" refers to a temperature of about 15°C to about 30°C, more preferably, to a temperature of about 20°C to about 25°C.

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    Samples of crystalline composition containing GBPE and sugar-excipient such as lactose monohydrate, mannitol and sorbitol were prepared according to the processes described below. The samples, which were analyzed by X-Ray Powder diffraction ("XRPD"), are characterized by XRPD substantially as depicted in figure 1. Preferably, the sugar excipient is lactose monohydrate.

Figure 1: A characteristic XRPD of crystalline composition containing GBPE and lactose monohydrate

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According to figure 1 the crystalline composition containing GBPE and lactose monohydrate is characterized by XRPD peaks at about 9.0, 12.4, 13.6, 18.6 and 19.5 degrees two theta ± 0.2 degrees two theta. The crystalline composition may be further characterized by an XRPD having additional peaks at about: 14.1, 16.4, 18.1, 21.0, 23.3 and 27.3 degrees two theta ± 0.2 d...