Asymmetry Effect of Particle Size Distribution on Content Uniformity and Over-Potency Risk in Low-Dose Solid Drugs

• Published in: Journal of pharmaceutical sciences Vol. 99; no. 10; pp. 4351 - 4362
• Main Authors: Huang, Chien-Yueh, Sherry Ku, M.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.10.2010; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Biological and medical sciences; content uniformity; Decay; Dose-Response Relationship, Drug; Drugs; General pharmacology; heavy tail; log- skew-normal distribution; low-dose drugs; Medical sciences; Models, Theoretical; Monte Carlo Method; Monte-Carlo; over potency; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Risk; content uniformity; particle size; heavy tail; log- skew-normal distribution; over potency; Monte-Carlo; low-dose drugs; Drug; Monte Carlo method; Particle size; Pharmaceutical technology; Low dose; Normal; Particle size distribution; Content; log-skew-normal distribution; Size effect; Risk factor; Monte—Carlo; Uniformity
• ISSN: 0022-3549; 1520-6017; 1520-6017
• DOI: 10.1002/jps.22128

Most active pharmaceutical ingredients (API) exhibit particle size distributions with some degrees of asymmetry deviating from log-normality. A new log-skew-normal (L-S-N) distribution model is proposed for a systematic comparison of the asymmetry effect on content uniformity. The new model originated from the S-N model used by Azzalini gives a close approximation to real API particle size distribution. Monte-Carlo method was employed to simulate the dosage potency distribution. A high risk of over potency is uncovered when either the dose is low or API particle size distribution is positively skewed. This is due to the formation of pseudo heavy tail in potency distribution that decays slower than exponentially. Nomographs of API particle size versus dosage strength were constructed with a range of geometric standard deviations and asymmetry parameters with and without particle size cut-off (sieving) for a combined 99% pass rate against USP Uniformity of Dosage Units. It was found that for a given specification of volume median and 90% diameters (d50 and d90), the dosage strength must increase by 10 times if the API asymmetry parameter changes from 1 (log-normal) to 1.1.