title: Investigation of physicochemical factors affecting the stability of a pH-modulated solid dispersion and a tablet during storage.
abstract: The stability of solid dispersions (SD) during storage is of concern. We prepared the pH-modulated SD (pSD) and compressed tablets consisting of polyethylene glycol (PEG) 6000 as a carrier, drug and MgO (alkalizer). Telmisartan (TEL), an ionizable poorly water-soluble drug, was chosen as a model drug. The changes in physicochemical factors such as the dissolution rate, drug crystallinity, microenvironmental pH (pH(M)) and intermolecular interactions of the pSD and the tablets were investigated over 3 months under different temperature and relative humidity (RH) conditions: refrigerator (5-8 °C), 25 °C/32% RH, 25 °C/55% RH, 25 °C/75% RH, 40°C/32% RH, 40 °C/55% RH, and 40 °C/75% RH. Differential scanning calorimetry (DSC) analysis of all samples revealed no distinct changes in the drug melting point. In contrast, powder X-ray diffraction (PXRD) diffractograms revealed that samples stored at 40 °C/75% RH for 1 month, 25 °C/75% RH for 3 months and 40 °C at all humidity conditions for 3 months showed gradual recrystallization of the drug. Fourier transform infrared (FTIR) spectra indicated a reduced intensity of intermolecular interactions between TEL and MgO in the pSD and tablet. The pH(M) also gradually decreased. These altered physicochemical factors under the stressed conditions resulted in decreased dissolution profiles in intestinal fluid (pH 6.8). In contrast, the dissolution rate in gastric fluid (pH 1.2) was almost unchanged because of the high intrinsic solubility of TEL at this pH.
authors.affiliation: Bioavailability Control Laboratory, College of Pharmacy, Kangwon National University, Chuncheon 200-701, Republic of Korea.
authors.forename: Phuong Ha-Lien
authors.initials: PH
authors.lastname: Tran
authors.forename: Thao Truong-Dinh
authors.initials: TT
authors.lastname: Tran
authors.forename: Jun-Bom
authors.initials: JB
authors.lastname: Park
authors.forename: Dong Hun
authors.initials: DH
authors.lastname: Min
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
authors.forename: Yun-Seok
authors.initials: YS
authors.lastname: Rhee
authors.forename: Beom-Jin
authors.initials: BJ
authors.lastname: Lee
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry; D001562:Benzimidazoles / Q000737:chemistry; D001565:Benzoates / Q000737:chemistry; D055598:Chemical Phenomena; D003460:Crystallization; D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D004356:Drug Storage; D005079:Excipients / Q000737:chemistry; D006813:Humidity; D008277:Magnesium Oxide / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012995:Solubility; D013535:Suspensions / Q000737:chemistry; D013607:Tablets / Q000737:chemistry*; D000077333:Telmisartan; D013696:Temperature
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D005079:Excipients; D013535:Suspensions; D013607:Tablets; D008277:Magnesium Oxide; D011092:Polyethylene Glycols; D000077333:Telmisartan