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

• Published in: International journal of pharmaceutics 2017-04, Vol.522 (1-2), p.74-79
• Main Authors: Jensen, Linda G., Skautrup, Frederik B., Müllertz, Anette, Abrahamsson, Bertil, Rades, Thomas, Priemel, Petra A.
• Format: Article
• Language: English
• Subjects: Amorphous; Carbamazepine; Carbamazepine - chemistry; Crystallization; Dihydrate; Dissolution; Drug Compounding; Drug Liberation; Hypromellose Derivatives; Intestines - metabolism; Pharmaceutical Solutions; Povidone; Solubility; Supersaturation; X-Ray Diffraction
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2017.02.062

[Display omitted] 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 30min) and subsequently in intestinal conditions (for 2h). Carbamazepine form III in the absence of polymer dissolved to a drug concentration of 540μg/ml, but the concentration decreased after around 70min due to precipitation of the dihydrate form, and reached 436μg/ml after 2.5h 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 (290–310μg/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 408μg/ml after 2.5h, i.e. lower than for the crystalline drug, whilst glass solutions with HPMC reached concentrations similar to the crystalline drug.