Enhanced Physical Stability of Amorphous Drug Formulations via Dry Polymer Coating

Co-amorphous drug delivery systems (CAMS) are characterized by the combination of two or more (initially crystalline) low molecular weight components that form a homogeneous single-phase amorphous system. Over the past decades, CAMS have been widely investigated as a promising approach to address the challenge of low water solubility of many active pharmaceutical ingredients. Most of the studies on CAMS were performed on a case-by-case basis, and only a few systematic studies are available. A quantitative analysis of the literature on CAMS under certain aspects highlights not only which aspects have been of great interest, but also which future developments are necessary to expand this research field. This review provides a comprehensive updated overview on the current published work on CAMS using a quantitative approach, focusing on three critical quality attributes of CAMS, i.e., co-formability, physical stability, and dissolution performance. Specifically, co-formability, molar ratio of drug and co-former, preparation methods, physical stability, and in vitro and in vivo performance were covered. For each aspect, a quantitative assessment on the current status was performed, allowing both recent advances and remaining research gaps to be identified. Furthermore, novel research aspects such as the design of ternary CAMS are discussed.

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Exploiting Kinetic Solubility Differences for Low Level Detection of Crystallinity in Amorphous Drug Formulations

Current Pharmaceutical Analysis ◽

10.2174/1573412915666181210144338 ◽

2020 ◽

Vol 16 (5) ◽

pp. 529-538

Author(s):

Gregory K. Webster ◽

Cynthia A. Pommerening ◽

Whitney W. Harman ◽

Mathew A. Gragg ◽

Jian-Hwa Han ◽

...

Keyword(s):

Dosage Form ◽

Amorphous State ◽

Analytical Techniques ◽

Drug Level ◽

Drug Substance ◽

Phase Iii ◽

Drug Formulations ◽

Total Recovery ◽

Amorphous Drug ◽

Kinetic Solubility

Background: Enabling formulations have been implemented by the pharmaceutical industry as an effective tool for keeping Active Pharmaceutical Ingredient (API) in an amorphous state. Upon dosing in the amorphous state, many drugs which fail to demonstrate bioactivity due to the limited solubility and bioavailability of their crystalline form become bioavailable. Purpose: The analytical techniques use today for crystallinity detection are challenged by the sensitivity and robustness needed to achieve a 5% quantitation limit in low dose drug products. Our laboratory has developed a novel procedure capable of meeting this sensitivity and selectivity requirement. This is achieved by exploiting the differences in kinetic solubility of the formulated amorphous and free crystalline forms of API currently being used in dosage form platforms. Methods: Representative amorphous drug formulations were prepared and spiked with varying levels of crystalline drug substances to evaluate the selectivity and recovery of the crystalline drug substance from the product formulation. Kinetic solubility testing using a (i) Particle wetting phase, (ii) Particle suspending/erosion phase, (iii) Sampling time point and (iv) A total recovery determination for the drug substance. Results: The method selectively and quantitatively distinguishes crystalline drug substance from amorphous drug substance for samples spiked from 2.5% to 10% of the nominal label concentration of the API in the dosage form matrix. Conclusion: The kinetic solubility approach reported here achieves sensitive crystallinity quantitation for low drug level amorphous drug formulations at levels not yet achieved by complimentary analytical techniques.

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Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2017.08.123 ◽

2017 ◽

Vol 532 (1) ◽

pp. 1-12 ◽

Cited By ~ 40

Author(s):

Riikka Laitinen ◽

Korbinian Löbmann ◽

Holger Grohganz ◽

Petra Priemel ◽

Clare J. Strachan ◽

...

Keyword(s):

Drug Delivery ◽

Drug Delivery Systems ◽

Delivery Systems ◽

Drug Formulations ◽

Amorphous Drug

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A slow cooling rate of indomethacin melt spatially confined in microcontainers increases the physical stability of the amorphous drug without influencing its biorelevant dissolution behaviour

Drug Delivery and Translational Research ◽

10.1007/s13346-013-0166-7 ◽

2013 ◽

Vol 4 (3) ◽

pp. 268-274 ◽

Cited By ~ 9

Author(s):

Line Hagner Nielsen ◽

Stephan Sylvest Keller ◽

Anja Boisen ◽

Anette Müllertz ◽

Thomas Rades

Keyword(s):

Cooling Rate ◽

Physical Stability ◽

Slow Cooling ◽

Biorelevant Dissolution ◽

Dissolution Behaviour ◽

Amorphous Drug

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Hot Melt Coating of Amorphous Carvedilol

Pharmaceutics ◽

10.3390/pharmaceutics12060519 ◽

2020 ◽

Vol 12 (6) ◽

pp. 519 ◽

Cited By ~ 1

Author(s):

Jacob Bannow ◽

Lina Koren ◽

Sharareh Salar-Behzadi ◽

Korbinian Löbmann ◽

Andreas Zimmer ◽

...

Keyword(s):

Drug Release ◽

Physical Stability ◽

Spray Coating ◽

Aqueous Solubility ◽

Immediate Release ◽

In Vitro Lipolysis ◽

Drug Candidates ◽

Amorphous Drug ◽

Hot Melt

The use of amorphous drug delivery systems is an attractive approach to improve the bioavailability of low molecular weight drug candidates that suffer from poor aqueous solubility. However, the pharmaceutical performance of many neat amorphous drugs is compromised by their tendency for recrystallization during storage and lumping upon dissolution, which may be improved by the application of coatings on amorphous surfaces. In this study, hot melt coating (HMC) as a solvent-free coating method was utilized to coat amorphous carvedilol (CRV) particles with tripalmitin containing 10% (w/w) and 20% (w/w) of polysorbate 65 (PS65) in a fluid bed coater. Lipid coated amorphous particles were assessed in terms of their physical stability during storage and their drug release during dynamic in vitro lipolysis. The release of CRV during in vitro lipolysis was shown to be mainly dependent on the PS65 concentration in the coating layer, with a PS65 concentration of 20% (w/w) resulting in an immediate release profile. The physical stability of the amorphous CRV core, however, was negatively affected by the lipid coating, resulting in the recrystallization of CRV at the interface between the crystalline lipid layer and the amorphous drug core. Our study demonstrated the feasibility of lipid spray coating of amorphous CRV as a strategy to modify the drug release from amorphous systems but at the same time highlights the importance of surface-mediated processes for the physical stability of the amorphous form.

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