The preparation and evaluation of salt forms of linogliride with reduced solubilities as candidates for extended release

Abstract

Salts of linogliride with reduced solubilities were prepared and evaluated as potential candidates for extended-release oral dosage forms. A once-daily dose of 300–800 mg was intended. Seven acids were selected: p-acetamidobenzoic, benzoic, p-hydroxybenzoic, 3-hydroxy-2-naphthoic, 1-napsylic, pamoic, and p-toluenesulfonic acids but only four salts were able to be prepared in suitable quantities for evaluation: linogliride pamoate, p-hydroxybenzoate, 3-hydroxy-2-naphthoate, and 1-napsylate. The pH-solubility profiles of the four new salts, free base, and fumarate salt were compared over the pH 1.43–8.3 range and the intrinsic dissolution rates of the four new salts and the free base were determined at pH 1.43, 4.4, and 7.5. The range of the pH-solubility profile and intrinsic dissolution rates of the p-hydroxybenzoate salt were less than the free base and fumarate and higher than the other three new salts. The pH-solubilities and intrinsic dissolution rates of the 1-napsylate salt were pH-independent. The solubilities and intrinsic dissolution rates of the pamoate and 3-hydroxy-2-naphthoate were higher at pH 1.4–3.4 than at higher pH. At pH 4.4 and higher, the solubilities were essentially the same, in the 1–2 mg/mL range. The intrinsic dissolution rates were also very low and not very different. Dissolution studies with capsules containing 800 mg doses of the pamoate, 1-napsylate, free base, and fumarate performed in a dissolution medium of pH beginning at 2.2 and ending at 6.8 demonstrated that the pamoate and 1-napsylate salt forms dissolved slower and could be useful as extended-release forms.

Keywords:

• Extended release
• poorly soluble salts
• pH-solubility profile
• intrinsic dissolution rate

Acknowledgements

The authors are grateful to

Mr. Martin Mutter for his assistance for determining the stoichiometry of the salts by NMR and calculations entailed in elemental analysis.

Mr. Barry Fegely for his help, suggestions, and technical assistance.

Dr. W. Douglas Walkling, Director of Physical Pharmacy and McNeil Pharmaceutical, for providing the co-op opportunity that included laboratory facilities, funding, and a stipend for support while Mr. Kaleem Ahmad was on site at McNeil Pharmaceutical, Spring House, PA.

The work presented here represents in part the laboratory and MS thesis requirements of Kaleem Ahmad for the completion of his MS degree in Cosmetic Science, College of Pharmacy, and University of Cincinnati. It represents work performed by Dr. Frank Chrzanowski while serving as an Adjunct Professor at the College of Pharmacy, University of Cincinnati and Research Manager, Preformulation/Physical Pharmacy, Mc Neil Pharmaceutical, Spring House, PA.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.