Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid.

We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.

Development of a gradient elution preparative high performance liquid chromatography method for the recovery of the antibiotic ertapenem from crystallization process streams.

A gradient elution preparative chromatography method was developed for the recovery of the antibiotic ertapenem from crystallization mother-liquor streams. The preparative HPLC method that was developed on the lab-scale employs an analytical size column of conventional dimensions (25 cm x 0.46 cm) packed with Kromasil C8 stationary phase. Gradient elution was used with aqueous acetic acid and acetonitrile as mobile phases. A target of processing approximately 30 mg of ertapenem per half an hour at a flow rate of 1.5 mL/min with high yield and adequate rejection of all major impurities was achieved. This corresponds to a productivity of approximately 0.6 kg ertapenem as free acid per kilogram of stationary phase per day (kkd). The scalability of the method was demonstrated by using a 5 cm i.d. column configuration to generate 10 g of purified ertapenem. This work complements a previous study improving on the productivity and throughput of the method by employing gradient elution and the use of crystallization to remove some key impurities that are chromatographically difficult to resolve [A. Vailaya, P. Sajonz, O. Sudah, V. Capodanno, R. Helmy, F.D. Antia, J. Chromatogr. A 1079 (2005) 80].

Challenges in the analytical method development and validation for an unstable active pharmaceutical ingredient.

A sensitive high-performance liquid chromatography (HPLC) impurity profile method for the antibiotic ertapenem is developed and subsequently validated. The method utilizes an Inertsil phenyl column at ambient temperature, gradient elution with aqueous sodium phosphate buffer at pH 8, and acetonitrile as the mobile phase. The linearity, method precision, method ruggedness, limit of quantitation, and limit of detection of the impurity profile HPLC method are found to be satisfactory. The method is determined to be specific, as judged by resolving ertapenem from in-process impurities in crude samples and degradation products that arise from solid state thermal and light stress, acid, base, and oxidative stressed solutions. In addition, evidence is obtained by photodiode array detection studies that no degradate or impurity having a different UV spectrum coeluted with the major component in stressed or unstressed samples. The challenges during the development and validation of the method are discussed. The difficulties of analyzing an unstable active pharmaceutical ingredient (API) are addressed. Several major impurities/degradates of the API have very different UV response factors from the API. These impurities/degradates are synthesized or prepared by controlled degradation and the relative response factors are determined.