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Solvent-Casted Films to Assist Polymer Selection for Amorphous Solid Dispersions During Preclinical Studies: In-vitro and In-vivo Exploration

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Abstract

Purpose

The use of two solvent-casted film methods to select optimal polymer compositions for amorphous solid dispersions prepared to support preclinical pharmacokinetic and toxicology studies is described.

Methods

Evaporation of solvent from cover slips by using nitrogen flow, and solvent removal from vials by using rotary evaporation were employed. The films prepared on cover slips were evaluated under the microscope to determine crystallinity. The methods were validated by scaling up corresponding SDDs, evaluating SDD’s dissolution, and comparing those results to the dissolution of drug-polymer films. Subsequently, SDD suspensions were prepared and dosed orally to rats to determine pharmacokinetic parameters. This was done by using three compounds from our pipeline and evaluating multiple polymers.

Results

The dissolution of generated films showed good agreement with the dissolution of spray dried dispersions when the films were fully amorphous (Compound A and B). In contrast, there was disagreement between film and SDD dissolution when the films had crystallized (Compound C). The in vivo exposure results indicated that the polymer choice based on the film screening methods would have been accurate for drug-polymer films that were amorphous (Compound A and B). Two additional case studies (Compound D and E) are presented, showing good agreement between in vivo and in vitro results.

Conclusion

This study established the ability of two film casting screening methods to predict the in vitro and in vivo performance of corresponding SDDs, provided that the films are fully amorphous.

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Abbreviations

ASD:

Amorphous solid dispersion

CAP:

Cellulose acetate phthalate

FaSSIF:

Fasted state simulated intestinal fluid

HPMC:

Hydroxypropyl methylcellulose

HPMC-AS:

Hydroxypropyl methylcellulose acetate succinate

HPMC-HP:

Hydroxypropyl methylcellulose phthalate

NF:

Nitrogen flow

PBS:

Phosphate buffer saline

PK:

Pharmacokinetics

PVAP:

Polyvinyl acetate phthalate

RE:

Rotary evaporation

SC:

Spin Coating

SDD:

Spray dried dispersion

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Authors and Affiliations

  1. Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Route 206 and Province Line Road, Princeton, NJ, 08540, USA

    Laura I. Mosquera-Giraldo, Maria Donoso, Kevin Stefanski, Kimberly Foster, Christoph Gesenberg, Pamela Abraham, Ying Ren, Anne Rose, Chris Freeden & Asoka Ranasinghe

Authors
  1. Laura I. Mosquera-Giraldo
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  2. Maria Donoso
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  3. Kevin Stefanski
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  4. Kimberly Foster
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  5. Christoph Gesenberg
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  6. Pamela Abraham
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  7. Ying Ren
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  8. Anne Rose
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  9. Chris Freeden
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  10. Asoka Ranasinghe
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Correspondence to Laura I. Mosquera-Giraldo.

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Supplementary Information

ESM 1

Additional Information can be found in the supplemental material: bioanalysis methods, chromatography methods for in vitro dissolution experiments; pharmacokinetic parameters corresponding to analysis of compound A, B, and C; classification of compound A, B, C and E in the Tm/Tg versus Log P diagram; characterization of polymer films; powder X-ray diffraction results for compound C SDDs; microscopy film pictures for Compound D and E; and description of polymer composition. (DOCX 6830 kb)

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Mosquera-Giraldo, L.I., Donoso, M., Stefanski, K. et al. Solvent-Casted Films to Assist Polymer Selection for Amorphous Solid Dispersions During Preclinical Studies: In-vitro and In-vivo Exploration. Pharm Res 38, 901–914 (2021). https://doi.org/10.1007/s11095-021-03040-w

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  • DOI: https://doi.org/10.1007/s11095-021-03040-w

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