Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality

Frank, Derek S.; Matzger, Adam J.

doi:10.1021/acs.molpharmaceut.8b00219

Cited by 51 publications

(33 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These observations are consistent with the work of Matzger on using polymer templating to control the physical form of APIs. [35][36][37][38][39] This has also led to the generation of previously unknown polymorphs, for instance of phenobarbital. 40 The isolation of olanzapine form IV in this study demonstrates that it is possible to obtain metastable forms with reasonable chemical and physical purity by heating amorphous solid dispersions of drug in polymer.…”

Section: Extraction Of Form IV and Further Characterizationmentioning

confidence: 99%

Olanzapine Form IV: Discovery of a New Polymorphic Form Enabled by Computed Crystal Energy Landscapes

Askin¹,

Cockcroft²,

Price³

et al. 2019

Crystal Growth & Design

View full text Add to dashboard Cite

Olanzapine is a polymorphic drug molecule that has been extensively studied, with over 60 structures reported in the Cambridge Structural Database. All anhydrous and solvated forms of olanzapine known to date contain the SC0 dimer packing motif. In this study, a new screening approach was adopted involving heat-induced forced crystallization from a polymer-based molecular dispersion of olanzapine. Simultaneous differential scanning calorimetry-powder X-ray diffraction (DSC-PXRD) was used to heat the amorphous dispersion and to identify a novel physical form from diffraction and heat flow data. Comparison of the diffraction data with those from a computed crystal energy landscape allowed the crystal structure to be determined. The result was the discovery of a new polymorph, form IV, which does not use the SC0 motif. Hence, while dimer formation is the dominant process that defines crystal packing for olanzapine formed from solution, it seems that molecularly dispersing the drug in a polymeric matrix permits crystallization of alternative motifs. Having identified form IV, it proved possible to scale up the synthesis and demonstrate its enhanced dissolution properties over form I.

show abstract

Section: Extraction Of Form IV and Further Characterizationmentioning

confidence: 99%

Olanzapine Form IV: Discovery of a New Polymorphic Form Enabled by Computed Crystal Energy Landscapes

Askin¹,

Cockcroft²,

Price³

et al. 2019

Crystal Growth & Design

View full text Add to dashboard Cite

show abstract

“…ASDs stabilize the amorphous drug by dispersing it in the polymeric matrix; this prevents the drug from recrystallizing. 11 Moreover, the polymer controls the release of the amorphous drug from its matrix; this ensures the congruent release of the drug from the polymeric matrix, which prevents the recrystallization of the drug in the biological system. 12 The two most commonly utilized methods for the preparation of ASDs include hot-melt extrusion (HME) and Spray drying (SD), which are used for the majority of drugs, but they have significant limitations.…”

Section: Introductionmentioning

confidence: 99%

Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution Rate

Davis

Thakkar

et al. 2021

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

This study reports the development of ritonavir-copovidone amorphous solid dispersions (ASDs) and dosage forms thereof using selective laser sintering (SLS) 3-dimensional (3-D) printing in a single step, circumventing the post-processing steps required in common techniques employed to make ASDs. For this study, different drug loads of ritonavir with copovidone were processed at varying processing conditions to understand the impact, range, and correlation of these parameters for successful ASD formation. Further, ASDs characterized using conventional and advanced solid-state techniques including wide-angle X-ray scattering (WAXS), solid-state nuclear magnetic resonance (ssNMR), revealed the full conversion of the crystalline drug to its amorphous form as a function of laser-assisted selective fusion in a layer-by-layer manner. It was observed that an optimum combination of the powder flow properties, surface temperature, chamber temperature, laser speed, and hatch spacing was crucial for successful ASD formation, any deviations resulted in print failures or only partial amorphous conversion. Moreover, a 21fold increase in solubility was demonstrated by the SLS 3-D printed tablets. The results confirmed that SLS 3-D printing can be used as a single-step platform for creating ASD-based pharmaceutical dosage forms with a solubility advantage.

show abstract

“…13,14 In recent years, hydrophilic polymers, such as poly(ethylene glycol) (PEG), 15 poly(N-vinylpyrrolidone) (PVP), 16 poly(acrylic acid) derivatives, 17 and cellulose derivatives, 18 have been used, and it is known that the possible interaction between the drug molecules and polymers inhibits the crystallization in the solid state and contributes to stability enhancement of the supersaturated state. 19,20 Therefore, the following two characteristics are required for the carriers of solid dispersions to improve bioavailability: (1) the ability of the carrier to dissolve quickly and (2) the maintenance of the supersaturated state during its dissolution process and ability to work as a drug feeder interacting with hydrophobic drug molecules.…”

Section: Introductionmentioning

confidence: 99%

Chemical Structural Effects of Amphipathic and Water-soluble Phospholipid Polymers on Formulation of Solid Dispersions

Yoshie

Yada

Ando

et al. 2021

Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

For the polymeric carriers of solid dispersions, it is important that carriers themselves dissolve quickly and maintain the supersaturated state of amorphous drugs during their dissolution period to improve bioavailability. Amphipathic 2-methacryloyloxyethyl phosphorylcholine (MPC) polymers can be dissolved in water, owing to the extremely high hydrophilicity of the MPC units, and are used as an ideal feeder for drug molecules to form aggregates in aqueous conditions. We synthesized amphipathic MPC copolymers with different hydrophobic side chains and molar ratios of MPC units, and evaluated the effect of the polymers on dissolution rate and supersaturation maintenance of solid dispersions of indomethacin. In most of the water-soluble amphipathic MPC copolymers, "spring-parachute"-like dissolution behavior was observed, where the drug initially became supersaturated followed by slow precipitation. In particular, MPC copolymers with aromatic rings in their side chains or polymers with a high percentage of hydrophobic units remained in a supersaturated state for a longer period. In contrast, urethane groups, which form hydrogen bonds with drug molecules, could also interact with water and were not conducive to maintaining supersaturation. In addition, water solubility of the polymer is important for rapid dissolution.

show abstract

Probing the Interplay between Amorphous Solid Dispersion Stability and Polymer Functionality

Cited by 51 publications

References 55 publications

Olanzapine Form IV: Discovery of a New Polymorphic Form Enabled by Computed Crystal Energy Landscapes

Olanzapine Form IV: Discovery of a New Polymorphic Form Enabled by Computed Crystal Energy Landscapes

Selective Laser Sintering 3-Dimensional Printing as a Single Step Process to Prepare Amorphous Solid Dispersion Dosage Forms for Improved Solubility and Dissolution Rate

Chemical Structural Effects of Amphipathic and Water-soluble Phospholipid Polymers on Formulation of Solid Dispersions

Contact Info

Product

Resources

About