Increasing Drug Loading of Weakly Acidic Telmisartan in Amorphous Solid Dispersions through pH Modification during Hot-Melt Extrusion

Thompson, Stephen A.; Davis, Donald R.; Moon, Chaeho; Williams, Robert O.

doi:10.1021/acs.molpharmaceut.1c00805

Cited by 9 publications

(11 citation statements)

References 44 publications

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“…These outcomes are based on XRPD analyses, since XRPD was found to be more sensitive than mDSC within the scope of the physical stability assessment. Recent studies also reported the greater sensitivity of XRPD as compared to mDSC and attributed this to dissolution of the drug in the polymer during the heating procedure of mDSC [ 13 , 41 ]. In general, crystallinity could first be detected for the harshest stability condition (i.e., 40 °C/75% RH), followed by the medium 40 °C/0% RH condition.…”

Section: Resultsmentioning

confidence: 99%

“…An ASD or glass solution is, however, only thermodynamically stable (i.e., the drug will never crystallize), in case the drug content is below its thermodynamic solubility limit in the polymer [ 10 , 11 ]. The persisting trend to lower the pill burden to promote patient therapeutic compliance requires the implementation of as high as possible drug loadings within the polymer [ 5 , 12 , 13 ]. Such high drug-loaded ASDs can imply physical stability issues during down-stream processing, as well as during storage, and can therefore defeat the ASD solubility advantage [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

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The Value of Bead Coating in the Manufacturing of Amorphous Solid Dispersions: A Comparative Evaluation with Spray Drying

et al. 2022

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Despite the fact that an amorphous solid dispersion (ASD)-coated pellet formulation offers potential advantages regarding the minimization of physical stability issues, there is still a lack of in-depth understanding of the bead coating process and its value in relation to spray drying. Therefore, bead coating and spray drying were both evaluated for their ability to manufacture high drug-loaded ASDs and for their ability to generate physically stable formulations. For this purpose, naproxen (NAP)–poly(vinyl-pyrrolidone-co-vinyl acetate) (PVP-VA) was selected as an interacting drug–polymer model system, whilst naproxen methyl ester (NAPME)–PVP-VA served as a non-interacting model system. The solvent employed in this study was methanol (MeOH). First, a crystallization tendency study revealed the rapid crystallization behavior of both model drugs. In the next step, ASDs were manufactured with bead coating as well as with spray drying and for each technique the highest possible drug load that still results in an amorphous system was defined via a drug loading screening approach. Bead coating showed greater ability to manufacture high drug-loaded ASDs as compared to spray drying, with a rather small difference for the interacting drug–polymer model system studied but with a remarkable difference for the non-interacting system. In addition, the importance of drug–polymer interactions in achieving high drug loadings is demonstrated. Finally, ASDs coated onto pellets were found to be more physically stable in comparison to the spray dried formulations, strengthening the value of bead coating for ASD manufacturing purposes.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Value of Bead Coating in the Manufacturing of Amorphous Solid Dispersions: A Comparative Evaluation with Spray Drying

et al. 2022

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“…To date, studies on the effect of counterions on dissolution enhancement focus more on free base drugs ,,, than on free acid drugs. , In fact, poorly soluble free acid drugs occupy a significant percentage of commercial drugs , and drug candidates in development. − The success of enhancing the dissolution rates of free acid drugs by amorphous sodium salt was demonstrated for IMC and furosemide . Besides dissolution rate enhancement, it has been reported that the incorporation of strong bases into a free acid drug telmisartan dispersion successfully increased the achievable drug loading by hot melt extrusion . Further studies to test the effect of counterions on the dissolution performance of additional free acid drugs and other pharmaceutical advantages introduced by the counterions would be helpful for advancing amorphous formulation development.…”

Section: Discussionmentioning

confidence: 99%

“…47 Besides dissolution rate enhancement, it has been reported that the incorporation of strong bases into a free acid drug telmisartan dispersion successfully increased the achievable drug loading by hot melt extrusion. 56 Further studies to test the effect of counterions on the dissolution performance of additional free acid drugs and other pharmaceutical advantages introduced by the counterions would be helpful for advancing amorphous formulation development.…”

Section: = • + S S (1 10mentioning

confidence: 99%

Effect of Buffer pH and Concentration on the Dissolution Rates of Sodium Indomethacin–Copovidone and Indomethacin–Copovidone Amorphous Solid Dispersions

Chiang,

Tang,

Mao

et al. 2023

Mol. Pharmaceutics

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The incorporation of counterions into amorphous solid dispersions (ASDs) has been proven to be effective for improving the dissolution rates of ionizable drugs in ASDs. In this work, the effect of dissolution buffer pH and concentration on the dissolution rate of indomethacin–copovidone 40:60 (IMC–PVPVA, w/w) ASD with or without incorporated sodium hydroxide (NaOH) was studied by surface area-normalized dissolution to provide further mechanistic understanding of this phenomenon. Buffer pH from 4.7 to 7.2 and concentration from 20 to 100 mM at pH 5.5 were investigated. As the buffer pH decreased, the IMC dissolution rate from both ASDs decreased. Compared to IMC–PVPVA ASD, the dissolution rate decrease from IMCNa–PVPVA ASD was more resistant to the decrease of buffer pH. In contrast, while buffer concentration had a negligible impact on the IMC dissolution rate from IMC–PVPVA ASD, the increase of buffer concentration significantly reduced the IMC dissolution rate from IMCNa–PVPVA ASD. Surrogate evaluation of microenvironment pH modification by the dissolution of IMCNa–PVPVA ASD demonstrated the successful elevation of buffer microenvironment pH and the suppression of such pH elevation by the increase of buffer concentration. These results are consistent with the hypothesis that the dissolution rate enhancement by the incorporation of counterions originates from the enhanced drug solubility by ionization and the modification of diffusion layer pH in favor of drug dissolution. At the studied drug loading (∼40%), relatively congruent release between IMC and PVPVA was observed when IMC was ionized in ASD or in solution, highlighting the importance of studying the ionization effect on the congruent release of ASDs, especially when drug ionization is expected in vivo. Overall, this work further supports the application of incorporating counterions into ASDs for improving the dissolution rates of ionizable drugs when enabling formulation development is needed.

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“…Since the HME process exposes the API and polymer to high temperatures, it is reasonable to assume that very high melting temperatures or thermally labile APIs bear high risk, as often reported in the literature [ 21 , 22 ]. However, it must be emphasized that dissolving an API in a polymer is a thermodynamically driven process.…”

Section: Introductionmentioning

confidence: 99%

A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development

et al. 2022

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Several literature publications have described the potential application of active pharmaceutical ingredient (API)–polymer phase diagrams to identify appropriate temperature ranges for processing amorphous solid dispersion (ASD) formulations via the hot-melt extrusion (HME) technique. However, systematic investigations and reliable applications of the phase diagram as a risk assessment tool for HME are non-existent. Accordingly, within AbbVie, an HME risk classification system (HCS) based on API–polymer phase diagrams has been developed as a material-sparing tool for the early risk assessment of especially high melting temperature APIs, which are typically considered unsuitable for HME. The essence of the HCS is to provide an API risk categorization framework for the development of ASDs via the HME process. The proposed classification system is based on the recognition that the manufacture of crystal-free ASD using the HME process fundamentally depends on the ability of the melt temperature to reach the API’s thermodynamic solubility temperature or above. Furthermore, we explored the API–polymer phase diagram as a simple tool for process design space selection pertaining to API or polymer thermal degradation regions and glass transition temperature-related dissolution kinetics limitations. Application of the HCS was demonstrated via HME experiments with two high melting temperature APIs, sulfamerazine and telmisartan, with the polymers Copovidone and Soluplus. Analysis of the resulting ASDs in terms of the residual crystallinity and degradation showed excellent agreement with the preassigned HCS class. Within AbbVie, the HCS concept has been successfully applied to more than 60 different APIs over the last 8 years as a robust validated risk assessment and quality-by-design (QbD) tool for the development of HME ASDs.

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Increasing Drug Loading of Weakly Acidic Telmisartan in Amorphous Solid Dispersions through pH Modification during Hot-Melt Extrusion

Cited by 9 publications

References 44 publications

The Value of Bead Coating in the Manufacturing of Amorphous Solid Dispersions: A Comparative Evaluation with Spray Drying

The Value of Bead Coating in the Manufacturing of Amorphous Solid Dispersions: A Comparative Evaluation with Spray Drying

Effect of Buffer pH and Concentration on the Dissolution Rates of Sodium Indomethacin–Copovidone and Indomethacin–Copovidone Amorphous Solid Dispersions

A Hot-Melt Extrusion Risk Assessment Classification System for Amorphous Solid Dispersion Formulation Development

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