title: Design of experiments utilization to map the processing capabilities of a micro-spray dryer: particle design and throughput optimization in support of drug discovery.
abstract: There has been a growing interest in amorphous solid dispersions for bioavailability enhancement in drug discovery. Spray drying, as shown in this study, is well suited to produce prototype amorphous dispersions in the Candidate Selection stage where drug supply is limited. This investigation mapped the processing window of a micro-spray dryer to achieve desired particle characteristics and optimize throughput/yield. Effects of processing variables on the properties of hypromellose acetate succinate were evaluated by a fractional factorial design of experiments. Parameters studied include solid loading, atomization, nozzle size, and spray rate. Response variables include particle size, morphology and yield. Unlike most other commercial small-scale spray dryers, the ProCepT was capable of producing particles with a relatively wide mean particle size, ca. 2-35 µm, allowing material properties to be tailored to support various applications. In addition, an optimized throughput of 35 g/hour with a yield of 75-95% was achieved, which affords to support studies from Lead-identification/Lead-optimization to early safety studies. A regression model was constructed to quantify the relationship between processing parameters and the response variables. The response surface curves provide a useful tool to design processing conditions, leading to a reduction in development time and drug usage to support drug discovery.
authors.affiliation: Merck Sharp & Dohme Corp. Merck Research Laboratories, Whitehouse Station, NJ, USA. james_ormes@merck.com
authors.forename: James D
authors.initials: JD
authors.lastname: Ormes
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.forename: Alex M
authors.initials: AM
authors.lastname: Chen
authors.forename: Shirley
authors.initials: S
authors.lastname: Hou
authors.forename: Davida
authors.initials: D
authors.lastname: Krueger
authors.forename: Todd
authors.initials: T
authors.lastname: Nelson
authors.forename: Allen
authors.initials: A
authors.lastname: Templeton
mesh_terms: D001682:Biological Availability; D004304:Dosage Forms; D004339:Drug Compounding / Q000295:instrumentation / Q000379:methods*; D015195:Drug Design; D055808:Drug Discovery; D005079:Excipients / Q000737:chemistry*; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D010316:Particle Size; D012044:Regression Analysis; D013997:Time Factors
chemical_list: D004304:Dosage Forms; D005079:Excipients; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose