Salt form selection and characterization of LY333531 mesylate monohydrate

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Abstract

LY333531 is a potent protein kinase Cβ (PKCβ) inhibitor currently under development for the treatment of diabetic complications. Seven salts of LY333531 (hydrochloride, sulfate, mesylate, succinate, tartrate, acetate and phosphate) were evaluated during the early phase of development. Physical property screening techniques including microscopy, DSC, TGA, XRPD, hygroscopicity and solubility were utilized to narrow the selection to two salts: the mesylate and hydrochloride. Identification of the optimal salt form was based upon solubility, bioavailability, physical stability and purity. During the evaluation process three hydrated forms (anhydrate, monohydrate, and tetrahydrate) of the hydrochloride salt were identified. The mesylate salt was found to give only one, a monohydrate. Processing parameters (e.g. filtration rate, crystal form stability) demonstrated that the anhydrate was the preferred form of the hydrochloride salt. Bioavailability studies in dogs indicated that the Cmax and area under the plasma concentration vs. time curve (AUC) for LY333531 and its active metabolite, LY338522, following administration of the mesylate salt were approximately 2.6 times those obtained after the LY333531 HCl dose. This difference was presumed to be due primarily to the fact that the mesylate was five times more soluble than the hydrochloride salt in water. These factors led to selection and development of LY333531 mesylate monohydrate as the active pharmaceutical ingredient for clinical evaluation.

Introduction

There has been a strong historical trend in the pharmaceutical industry to market the hydrochloride salt of amines. From an early literature review by Berge et al. (1977) nearly 43% of the FDA commercially marketed salts were hydrochlorides. Only about 2% have been marketed as mesylate salts. More recently Bighley et al. (1996) compiled data from drug monographs listed in the 1993 edition of Martindale, the Extra Pharmacopeia, that showed a similar percentage of hydrochloride and mesylate salts (44 vs. 3.2%). Although the hydrochloride salts of pharmaceutical bases have advantages over other salt forming moieties because of their low molecular weight and low toxicity, they can have potential issues. The primary concern is from a decrease in solubility as a result of chloride anion common ion effects in the stomach. This was described by Miyazaki et al. (1981) and more recently by Thomas et al. (1996). Recent trends have indicated that mesylate salts are becoming more common as the marketed active pharmaceutical ingredient. Looking at the new chemical entities approved by the FDA over the last five years that had associated anionic salts, nearly 20% were reported to be mesylate salts (compiled from information found using the FDA website (www.fda.gov)). Explanations for the current increase in the number of mesylate salts have not been disclosed in the literature.

In addition, studies comparing the salt forms of basic drugs have been limited, and none have reported significant differences in bioavailability between different salt forms. Lin et al. (1972) reported no enhancement in bioavailability when salts of a basic antihypertensive agent, having significantly different intrinsic dissolution rates, were compared. Walmsley et al. (1986) also indicated that they did not observe a difference in the extent of bioavailability between oxalate and citrate salts of naftidrofuryl and Jamuludin et al. (1988) saw no significant differences in Cmax, Tmax, or AUC of the hydrochloride, sulfate, and ethyl carbonate salts of quinine.

In this manuscript we will disclose our results from a salt selection study preformed on LY333531 (Scheme 1), a free base of very low aqueous solubility, in which a salt form for the drug product was required in order to enhance solubility and increase bioavailability. LY333531 has recently been identified as a competitive reversible inhibitor of protein kinsae Cβ and is being evaluated for the treatment of diabetic complications (e.g. retinopathy, erectile dysfunction) Ishii et al. (1996), Jirousek et al. (1996). Small lots (≤1 g) of seven salts (hydrochloride, sulfate, mesylate, succinate, tartrate, acetate, and phosphate) were initially crystallized and evaluated. Physical property tests including polarizing microscopy, hygroscopicity, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), X-ray powder diffraction (XRPD), and aqueous solubility were performed on each of these salt forms to consider the feasibility of further development. Similar tiered approaches have been described in the literature by Morris et al. (1994). Five salts (sulfate, succinate, tartrate, acetate and phosphate) were then eliminated due to poor crystallinity, low solubility and difficulty in improving the chemical purity during preparation. A comprehensive analysis of the remaining two salts mesylate and hydrochloride, were finally assessed evaluating additional parameters including polymorphism/hydrate formation, stability, purification, filterability and the relative bioavailability in dogs. The results obtained from this analysis, and outlined in this manuscript, have led us to develop the mesylate salt as the optimal salt form of LY333531.

Section snippets

Preparation of LY333531·mesylate monohydrate

The mesylate monohydrate salt of LY333531 was initially crystallized from methanol/water. However, the potential to generate methyl methanesulfonate, a known mutagen, in methanol caused us to examine alternative solvent systems. It was determined that acetone/water (9/1 v/v) was a more appropriate solvent combination for processing and all of the subsequent development lots were prepared using these conditions.

Preparation of LY333531 anhydrate, hydrated hydrochloride

The anhydrate and hydrated forms of the hydrochloride salt of LY333531 were

Physicochemical tests/results

Both salts displayed birefringence under the polarizing microscope and were observed as thin plates with varying degrees of agglomeration. Visually the salts were red or red-orange in color.

Aqueous solubility of mesylate and the hydrochloride were 0.5 and 0.1 mg/ml (as LY333531), respectively. The solubility of the free base in water was below the HPLC limits of detection (<1 μg/ml). Recent results from CaCO-2 screening and solubility testing in simulated gastric and intestinal fluids (M.

Conclusion

A systematic two-tier approach has been applied to the selection of the optimum salt form of LY333531 in an expeditious manner. Initial evaluation of the physical properties of seven salt forms of LY333531 (hydrochloride, sulfate, mesylate, succinate, tartrate, acetate, and phosphate) led us to select the mesylate and hydrochloride as potential salts for development. Comprehensive analysis of these two salt forms indicated that the mesylate monohydrate salt was more soluble (5X), more stable

Acknowledgements

The authors would like to thank Dr Sally Anliker, Mr. Joseph Kennedy and Mr. Edward Groleau for their assistance in providing analytical support.

References (11)

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