Research ArticlesCharacterization of amorphous API:Polymer mixtures using X-ray powder diffraction
Section snippets
INTRODUCTION
In recent years it has become apparent that in the early stages of the drug development process, as potential new drug candidates are being evaluated, more and more of those compounds showing in vitro efficacy through high affinity preferential binding to desired receptors and biomarkers and the potential for desirable in vivo performance, tend to exhibit very poor aqueous solubility. Such behavior is believed to arise because higher affinities of API from aqueous solution for biomarkers and
Materials
Indomethacin, polyvinylpyrrolidone K90, and dextran (Mn: 64–76 kDa) were obtained from Sigma (St. Louis, MO). D(+)-trehalose dihydrate was obtained from Fluka (Steinheim, GER). Solvents used to prepare dispersions, namely water and dichloromethane were obtained from Mallinckrodt (Phillipsburg, NJ) and EMD (Gibbstown, NJ), respectively, and used as received.
Dextran–PVP
The first system investigated was dextran–PVP dispersions prepared by freeze-drying. The individual components were analyzed initially to form a basis for comparison with the dispersion samples. Dextran used in this study (Mn: 64–76 kDa) exhibited a Tg onset value of 221°C as measured by mDSC. A Tg value of 211°C has been reported for dextran T10 (average molecular weight 9300) and 225°C has been reported for dextran T500 (average molecular weight 520,000),8 therefore the value obtained in this
DISCUSSION
The results of this study, as summarized in Table 1, demonstrate the need to support the use of DSC analysis to ascertain whether or not a mixture of amorphous components is miscible or immiscible by using a technique that more directly characterizes the structural features of such a system. Since thermal analysis and the measurement of Tg for polymers has been typically described as a measure of the diffusional relaxation kinetics of an amorphous molecule, it can not distinguish phase
CONCLUSIONS
This study has demonstrated that it is not always possible to determine whether an API–polymer amorphous mixture, processed with the intent of producing an amorphous molecular dispersion, is miscible or phase separated based only on the determination of Tg using DSC; one Tg apparently indicates a single amorphous phase and two Tg values indicate phase separation of amorphous phases. Evidence is presented, using XRPD measurements of individual components and those of the solid dispersion
Acknowledgements
The authors gratefully acknowledge the analytical support provided by SSCI Analytical Resources, Paul Schields, Claire Gendron, and Kevin Leach, for their assistance in acquiring the data used in this analysis.
REFERENCES (30)
Solid dispersion of poorly water soluble drugs: Early promises, subsequent problems, and recent breakthroughs
J Pharm Sci
(1999)- et al.
Mixing behavior of co-lyophilized binary amorphous systems
J Pharm Sci
(1998) - et al.
Combining SEM, TEM, and micro-Raman techniques to differentiate between the amorphous molecular level dispersions and nanodispersions of a poorly water-soluble drug within a polymer matrix
Int J Pharm
(2007) - et al.
High-resolution atomic distribution functions of disordered materials by high-energy X-ray diffraction
J Non-Cryst Solids
(2001) - et al.
Water vapor absorption into amorphous hydrophobic drug/poly(vinylpyrrolidone) dispersions
J Pharm Sci
(2002) - et al.
Inhibition of indomethacin crystallization in poly(vinylpyrrolidone) coprecipitates
J Pharm Sci
(1995) Solubility and solubilization in aqueous media
(1999)- et al.
Handbook of pharmaceutical salts: Properties, selection, and use
(2002) - et al.
Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API
Pharm Res
(2006) - et al.
What is the true solubility advantage for amorphous solids?
Pharm Res
(2000)
Spectroscopic characterization of interactions between PVP and indomethacin as amorphous molecular dispersions
Pharm Res
Non-isothermal and isothermal crystallization of sucrose from the amorphous state
Pharm Res
Phase separation in styrene-a-methyl styrene block copolymers
Two glass transitions do not necessarily indicate immiscibiity: The case of PEO/PMMA
J Polym Sci Part B Polym Phys
Local structure from diffraction
Cited by (170)
Use of Time-Domain NMR for <sup>1</sup>H T<inf>1</inf> Relaxation Measurement and Fitting Analysis in Homogeneity Evaluation of Amorphous Solid Dispersion
2024, Journal of Pharmaceutical SciencesConsiderations in the Development of Physically Stable High Drug Load API- Polymer Amorphous Solid Dispersions in the Glassy State
2023, Journal of Pharmaceutical SciencesFormulation and Processing Strategies which Underpin Susceptibility to Matrix Crystallization in Amorphous Solid Dispersions
2023, Journal of Pharmaceutical SciencesDescribing the Influence of Ball-milling on the Amorphization of Flubendazole Using the PDF and RMC Methods with X-ray Powder Diffraction Data
2022, Journal of Pharmaceutical SciencesRecent progress of amorphous and glassy coordination polymers
2022, Coordination Chemistry Reviews<sup>19</sup>F Solid-state NMR characterization of pharmaceutical solids
2022, Solid State Nuclear Magnetic Resonance
Ron C. Kelly’s present address is Amgen, South San Francisco, CA.