Citric acid monohydrate as a release-modifying agent in melt extruded matrix tablets.
Incomplete drug release and particle size-dependent dissolution performance can compromise the quality of controlled release matrix systems. The objective of the current study was to investigate the ability of citric acid monohydrate (CA MH) to enhance the release of diltiazem hydrochloride from melt extruded Eudragit RS PO tablets and to eliminate drug particle size effects. Preformulation studies demonstrated the thermal stability of all components, drug insolubility in the polymer but miscibility with the CA MH. Tablets with either constant polymer levels or constant drug-to-polymer ratios and containing different drug particle size fractions and increasing amounts of CA MH were manufactured by melt extrusion and characterized by dissolution testing, powder X-ray diffraction and scanning electron microscopy. The addition of CA MH to the formulation promoted the thermal processibility and matrix integrity by plasticization of the polymer. The drug release from systems with constant drug-to-polymer ratio was significantly increased when CA MH was added as a result of enhanced pore formation. Particle size effects were eliminated when large amounts of CA MH were used due to the loss of drug crystallinity. Matrix tablets with CA MH furthermore showed a faster and more complete drug release compared to systems with drug only or alternative pore formers (sucrose, NaCl, or PEG 3350). The enhanced drug release was attributed to the amorphous character of the soluble components, improved drug dispersion in the plasticized polymer along with increased polymer permeability. In summary, CA MH promoted the miscibility between the drug and Eudragit RS PO during hot-melt extrusion, resulting in the extrusion of an amorphous system with improved dissolution characteristics.
Schilling
Sandra U
SU
Drug Dynamics Institute, College of Pharmacy, University of Texas at Austin, Austin, TX 78712, USA. sschilling@mail.utexas.edu
Bruce
Caroline D
CD
Shah
Navnit H
NH
Malick
A Waseem
AW
McGinity
James W
JW
D002121:Calcium Channel Blockers / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D019343:Citric Acid / Q000737:chemistry*; D003460:Crystallization; D003692:Delayed-Action Preparations; D004110:Diltiazem / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D006358:Hot Temperature; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D011109:Polymethacrylic Acids / Q000737:chemistry; D033362:Powder Diffraction; D012995:Solubility; D013607:Tablets
D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D004337:Drug Carriers; C496966:Eudragit RSPO; D005079:Excipients; D011109:Polymethacrylic Acids; D013607:Tablets; D019343:Citric Acid; D004110:Diltiazem