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Revisit of solubility of oxytetracycline polymorphs. An old story in the light of new results.
Tempfli, Dóra; Borbás, Eniko; Pataki, Hajnalka; Csicsák, Dóra; Völgyi, Gergely; Sinkó, Bálint; Takács-Novák, Krisztina.
Afiliación
  • Tempfli D; Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9., Budapest H-1092 Hungary.
  • Borbás E; Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Muegyetem rakpart 3., Budapest, H-1111, Hungary.
  • Pataki H; Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Muegyetem rakpart 3., Budapest, H-1111, Hungary.
  • Csicsák D; Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9., Budapest H-1092 Hungary.
  • Völgyi G; Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9., Budapest H-1092 Hungary.
  • Sinkó B; Pion Inc. Billerica, Massachusetts 01821, United States.
  • Takács-Novák K; Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes Endre u. 9., Budapest H-1092 Hungary. Electronic address: novak.krisztina@pharma.semmelweis-univ.hu.
Eur J Pharm Sci ; 149: 105328, 2020 Apr 05.
Article en En | MEDLINE | ID: mdl-32268199
In the literature the therapeutic nonequivalence of oxytetracycline hydrochloride (OTCH) capsules and tablets was attributed to the different aqueous solubility of polymorphs without their comprehensive study. Our aim was to reveal the effects of polymorphism on equilibrium solubility, dissolution kinetics and the supersaturation of two OTCH polymorphs (stable Form A and metastable Form B).The equilibrium solubility was measured in biorelevant pH range 4-7.4 by the standardized saturation shake-flask method. We also studied the solubility in SGF at pH 1.2 and the effect of the pH change from 1.2 to 5.0 on solubility. The dissolution was studied using real-time concentration monitoring with an ATR probe attached to a UV spectrophotometer (µDISS Profiler). A wide spectrum of solid phase analysis methods (SEM, IR, XRPD, Raman) was applied for characterization of polymorphs and to identify which form is present at the equilibrium solubility. Identical equilibrium solubility values were obtained at the same pHs in region 4.0-7.4 using the two polymorphs as starting materials. The XRPD analysis of the isolated solid phases proved that both polymorphic forms were converted to dihydrate form. In situ monitoring of the dissolution at pH 5.0 showed immediate dissolution, no difference in supersaturation, and short equilibration time for both forms indicating the immediate conversion. In SGF (pH 1.2) Form B dissolved better than Form A and showed significantly different dissolution kinetic and stability. A long-lasting, false chain-citation stating that Form B dissolves 28x better in water than Form A, was cut by the present study (i) revealing that the cited data was measured in IPA not in water, and (ii) proving that only the intrinsic solubility of OTC dihydrate can be measured in water due to conversion of polymorphs under the experimental conditions of solubility measurement. However this conversion is inhibited below pH 1.5, so the differences in solubility and dissolution kinetic found at pH 1.2 may contribute to the interpretation of the different serum-levels reported at solid formulations.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article Pais de publicación: Países Bajos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Eur J Pharm Sci Asunto de la revista: FARMACIA / FARMACOLOGIA / QUIMICA Año: 2020 Tipo del documento: Article Pais de publicación: Países Bajos