Amorphous is not always better—A dissolution study on solid state forms of carbamazepine

Linda G. Jensen; Frederik B. Skautrup; Anette Müllertz; Bertil Abrahamsson; Thomas Rades; Petra A. Priemel

doi:10.1016/j.ijpharm.2017.02.062

Amorphous is not always better—A dissolution study on solid state forms of carbamazepine

Linda G. Jensen, Frederik B. Skautrup, Anette Müllertz, Bertil Abrahamsson, Thomas Rades^*, Petra A. Priemel

^*Corresponding author af dette arbejde

12 Citationer (Scopus)

Abstract

Poor aqueous solubility is a major concern for many new drugs. One possibility to overcome this issue is to formulate the drug as a high energy form, i.e. a metastable polymorph, an amorphous neat drug or a glass solution with polymers. In this study the dissolution properties of different solid state forms of carbamazepine, crystalline or amorphous drug, with or without either polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) and glass solutions of the drug with both polymers (2:1, 4:1 and 10:1 (w/w) drug-to-polymer ratio) were tested with respect to their dissolution behaviour in a biorelevant gastric medium (for 30 min) and subsequently in intestinal conditions (for 2 h). Carbamazepine form III in the absence of polymer dissolved to a drug concentration of 540 μg/ml, but the concentration decreased after around 70 min due to precipitation of the dihydrate form, and reached 436 μg/ml after 2.5 h dissolution testing. The presence of PVP led to a similar dissolution profile with a slightly earlier onset of decrease in drug concentration, while in the presence of HPMC no decline in dissolved drug concentration was observed. Surprisingly, amorphous carbamazepine did not result in any supersaturation and the drug concentration was lower than that measured for crystalline carbamazepine. The addition of polymers further decreased the concentration of dissolved drug (290–310 μg/ml, depending on polymer type and concentration). Amorphous drug converted quickly into the dihydrate form and thus no supersaturation was achieved. Glass solutions of carbamazepine with PVP reached drug concentrations between 348 and 408 μg/ml after 2.5 h, i.e. lower than for the crystalline drug, whilst glass solutions with HPMC reached concentrations similar to the crystalline drug.

Originalsprog	Engelsk
Tidsskrift	International Journal of Pharmaceutics
Vol/bind	522
Udgave nummer	1-2
Sider (fra-til)	74-79
Antal sider	6
ISSN	0378-5173
DOI	https://doi.org/10.1016/j.ijpharm.2017.02.062
Status	Udgivet - 30 apr. 2017

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10.1016/j.ijpharm.2017.02.062

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title = "Amorphous is not always better—A dissolution study on solid state forms of carbamazepine",

abstract = "Poor aqueous solubility is a major concern for many new drugs. One possibility to overcome this issue is to formulate the drug as a high energy form, i.e. a metastable polymorph, an amorphous neat drug or a glass solution with polymers. In this study the dissolution properties of different solid state forms of carbamazepine, crystalline or amorphous drug, with or without either polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) and glass solutions of the drug with both polymers (2:1, 4:1 and 10:1 (w/w) drug-to-polymer ratio) were tested with respect to their dissolution behaviour in a biorelevant gastric medium (for 30 min) and subsequently in intestinal conditions (for 2 h). Carbamazepine form III in the absence of polymer dissolved to a drug concentration of 540 μg/ml, but the concentration decreased after around 70 min due to precipitation of the dihydrate form, and reached 436 μg/ml after 2.5 h dissolution testing. The presence of PVP led to a similar dissolution profile with a slightly earlier onset of decrease in drug concentration, while in the presence of HPMC no decline in dissolved drug concentration was observed. Surprisingly, amorphous carbamazepine did not result in any supersaturation and the drug concentration was lower than that measured for crystalline carbamazepine. The addition of polymers further decreased the concentration of dissolved drug (290–310 μg/ml, depending on polymer type and concentration). Amorphous drug converted quickly into the dihydrate form and thus no supersaturation was achieved. Glass solutions of carbamazepine with PVP reached drug concentrations between 348 and 408 μg/ml after 2.5 h, i.e. lower than for the crystalline drug, whilst glass solutions with HPMC reached concentrations similar to the crystalline drug.",

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AU - Jensen, Linda G.

AU - Skautrup, Frederik B.

AU - Müllertz, Anette

AU - Abrahamsson, Bertil

AU - Rades, Thomas

AU - Priemel, Petra A.

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N2 - Poor aqueous solubility is a major concern for many new drugs. One possibility to overcome this issue is to formulate the drug as a high energy form, i.e. a metastable polymorph, an amorphous neat drug or a glass solution with polymers. In this study the dissolution properties of different solid state forms of carbamazepine, crystalline or amorphous drug, with or without either polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) and glass solutions of the drug with both polymers (2:1, 4:1 and 10:1 (w/w) drug-to-polymer ratio) were tested with respect to their dissolution behaviour in a biorelevant gastric medium (for 30 min) and subsequently in intestinal conditions (for 2 h). Carbamazepine form III in the absence of polymer dissolved to a drug concentration of 540 μg/ml, but the concentration decreased after around 70 min due to precipitation of the dihydrate form, and reached 436 μg/ml after 2.5 h dissolution testing. The presence of PVP led to a similar dissolution profile with a slightly earlier onset of decrease in drug concentration, while in the presence of HPMC no decline in dissolved drug concentration was observed. Surprisingly, amorphous carbamazepine did not result in any supersaturation and the drug concentration was lower than that measured for crystalline carbamazepine. The addition of polymers further decreased the concentration of dissolved drug (290–310 μg/ml, depending on polymer type and concentration). Amorphous drug converted quickly into the dihydrate form and thus no supersaturation was achieved. Glass solutions of carbamazepine with PVP reached drug concentrations between 348 and 408 μg/ml after 2.5 h, i.e. lower than for the crystalline drug, whilst glass solutions with HPMC reached concentrations similar to the crystalline drug.

AB - Poor aqueous solubility is a major concern for many new drugs. One possibility to overcome this issue is to formulate the drug as a high energy form, i.e. a metastable polymorph, an amorphous neat drug or a glass solution with polymers. In this study the dissolution properties of different solid state forms of carbamazepine, crystalline or amorphous drug, with or without either polyvinylpyrrolidone (PVP) or hydroxypropylmethylcellulose (HPMC) and glass solutions of the drug with both polymers (2:1, 4:1 and 10:1 (w/w) drug-to-polymer ratio) were tested with respect to their dissolution behaviour in a biorelevant gastric medium (for 30 min) and subsequently in intestinal conditions (for 2 h). Carbamazepine form III in the absence of polymer dissolved to a drug concentration of 540 μg/ml, but the concentration decreased after around 70 min due to precipitation of the dihydrate form, and reached 436 μg/ml after 2.5 h dissolution testing. The presence of PVP led to a similar dissolution profile with a slightly earlier onset of decrease in drug concentration, while in the presence of HPMC no decline in dissolved drug concentration was observed. Surprisingly, amorphous carbamazepine did not result in any supersaturation and the drug concentration was lower than that measured for crystalline carbamazepine. The addition of polymers further decreased the concentration of dissolved drug (290–310 μg/ml, depending on polymer type and concentration). Amorphous drug converted quickly into the dihydrate form and thus no supersaturation was achieved. Glass solutions of carbamazepine with PVP reached drug concentrations between 348 and 408 μg/ml after 2.5 h, i.e. lower than for the crystalline drug, whilst glass solutions with HPMC reached concentrations similar to the crystalline drug.

KW - Amorphous

KW - Carbamazepine

KW - Dihydrate

KW - Dissolution

KW - Supersaturation

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Amorphous is not always better—A dissolution study on solid state forms of carbamazepine

Abstract

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