title: Development of a nanofiltration process to improve the stability of a novel anti-MRSA carbapenem drug candidate.
abstract: The benzenesulfonate salt of an anti-methicillin-resistant Staphylococcus aureus carbapenem antibiotic studied is a crystalline, nonhygroscopic powder which is stable at room temperature, making it an ideal compound for long-term storage. However, the limited aqueous solubility of this salt prohibits parenteral administration. Conversely, the chloride salt of this carbapenem demonstrates opposing characteristics; it is quantitatively soluble in water, however is amorphous and subject to significant hydrolytic degradation in the solid state. Given two such extreme alternatives for pharmaceutical salt selection, a common approach taken is to develop the bioavailable salt and devise manufacturing and storage conditions that minimize degradation. This report describes a different approach to this manufacturing dilemma via the application of a simple and efficient nanofiltration process to convert the benzenesulfonate salt (storage entity) to the chloride salt (formulated drug product). Such an approach combines the positive attributes of these two salt forms into a single scalable process that reduces processing cycle times via elimination of redundant unit operations, increases the flexibility in manufacturing schedule, and improves overall product quality.
authors.affiliation: Merck Research Laboratories, Analytical Research, P.O. Box 2000, Mailcode RY818-B225, Rahway, New Jersey 07065, USA. vincent_antonucci@merck.com
authors.forename: V
authors.initials: V
authors.lastname: Antonucci
authors.forename: D
authors.initials: D
authors.lastname: Yen
authors.forename: J
authors.initials: J
authors.lastname: Kelly
authors.forename: L
authors.initials: L
authors.lastname: Crocker
authors.forename: E
authors.initials: E
authors.lastname: Dienemann
authors.forename: R
authors.initials: R
authors.lastname: Miller
authors.forename: O
authors.initials: O
authors.lastname: Almarrsson
mesh_terms: D001557:Benzenesulfonates / Q000737:chemistry*; D015780:Carbapenems / Q000737:chemistry*; D004355:Drug Stability; D005374:Filtration / Q000295:instrumentation / Q000379:methods; D016106:Methicillin Resistance; D036103:Nanotechnology / Q000295:instrumentation / Q000379:methods*; D013818:Thermogravimetry / Q000379:methods
chemical_list: D001557:Benzenesulfonates; D015780:Carbapenems; C032365:benzenesulfonic acid