Development and characterization of a scalable controlled precipitation process to enhance the dissolution of poorly water-soluble drugs.
OBJECTIVE
Poorly water-soluble compounds are being found with increasing frequency among pharmacologically active new chemical entities, which is a major concern to the pharmaceutical industry. Some particle engineering technologies have been shown to enhance the dissolution of many promising new compounds that perform poorly in formulation and clinical studies (Rogers et. al., Drug Dev Ind Pharm 27:1003-1015). One novel technology, controlled precipitation, shows significant potential for enhancing the dissolution of poorly soluble compounds. In this study, controlled precipitation is introduced; and process variables, such as mixing zone temperature, are investigated. Finally, scale-up of controlled precipitation from milligram or gram to kilogram quantities is demonstrated.


METHODS
Dissolution enhancement capabilities were established using two poorly water-soluble model drugs, danazol and naproxen. Stabilized drug particles from controlled precipitation were compared to milled, physical blend, and bulk drug controls using particle size analysis (Coulter), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), dissolution testing (USP Apparatus 2), and residual solvent analysis.


RESULTS
Stabilized nano- and microparticles were produced from controlled precipitation. XRD and SEM analyses confirmed that the drug particles were crystalline. Furthermore, the stabilized particles from controlled precipitation exhibited significantly enhanced dissolution properties. Residual solvent levels were below FDA limits.


CONCLUSIONS
Controlled precipitation is a viable and scalable technology that can be used to enhance the dissolution of poorly water-soluble pharmaceutical compounds.
Rogers
True L
TL
The Dow Chemical Company, Midland, Michigan 48674, USA. TLRogers@Dow.com
Gillespie
Ian B
IB
Hitt
James E
JE
Fransen
Kevin L
KL
Crowl
Cindy A
CA
Tucker
Christopher J
CJ
Kupperblatt
Gary B
GB
Becker
Joe N
JN
Wilson
Deb L
DL
Todd
Clifford
C
Broomall
Charles F
CF
Evans
Jonathan C
JC
Elder
Edmund J
EJ
D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002851:Chromatography, High Pressure Liquid; D003613:Danazol / Q000737:chemistry; D004339:Drug Compounding; D008855:Microscopy, Electron, Scanning; D008863:Microspheres; D009288:Naproxen / Q000737:chemistry; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012995:Solubility; D012997:Solvents; D014961:X-Ray Diffraction
D004364:Pharmaceutical Preparations; D012997:Solvents; D009288:Naproxen; D003613:Danazol