(T1530-12-72) Dissolution Rate Increases for Morphine Sulfate Extended-Release Drug Product When Mixed with High pH Soft Food for Long Contact Times

Purpose: Dysphagia is prevalent across sex and age groups in the US population [1, 2]. To ease the administration of solid dosage form of medications in the population affected by dysphagia, many drug products have labeling that describes how the product can be sprinkled over soft foods. A morphine sulfate extended-release formulation was selected as a model drug product to study 1) the physical changes of the product after it is sprinkled on soft food, 2) whether the physical changes in product could predict the change of the dissolution performance of the product, and 3) the impact of soft food viscosity, pH and contact of drug product with soft food on the dissolution performance.

Methods: Viscosity and pH of the soft foods were measured at 25℃ by a rheometer (Discovery HR 3 TA Instruments, DE, USA) and a pH meter (Orion Star A214 pH/ISE Meter, Thermo Scientific, MA, USA), respectively. Morphine sulfate extended-release (ER) pellets from capsules were sprinkled over soft foods (15 g), applesauce, apple juice, carrot puree, chocolate pudding, and vanilla yogurt, for contact times of 30 and 120 min. Pellets sprinkled in 0.1 N hydrochloric acid (pH 1.2 HCl), phosphate buffer (pH 7.5 PB), and artificial chocolate puddings of pH 1.2 and 7.5 were used for acidic  basic  and  controls, respectively, while non-sprinkled pellets were used as negative control in each experiment. Dissolution was performed with a 2-stage USP 1 dissolution test (1 h in 0.1 N HCl then 8.5 h in 7.5 PB) with a dissolution tester (VISION^® G2 ELITE 8^TM, Teledyne Hanson, CA, USA). Pellet mechanical strengths were measured using a texture analyzer (n=40, TA.XTplusC Texture Analyzer, Stable Micro Systems, London, UK). Water content was analyzed on a thermogravimeter (TGA Q500, TA Instruments, New Castle, DE, USA).  A screening design of experiments (DOE) was performed using JMP^® Pro 15 (SAS Institute Inc). Soft food pH, contact time, and viscosity were used as the primary factors on a screening DOE, and their interactions were also evaluated. The mean percent drug dissolved at 1 h in acid stage was chosen as the outcome to represent the dissolution profile.

Results: Viscosity measurements showed that all soft foods except apple juice were non-Newtonian and their measured viscosities are 0.518, 0.001, 0.758, 1.854, and 0.991 Pa·s for applesauce, apple juice, carrot puree, chocolate pudding, and vanilla yogurt, respectively, at shear rate 80 s^-1. Measured pH of applesauce, apple juice, carrot puree, chocolate pudding, and vanilla yogurt, were 3.63, 3.69, 4.98, 6.29, and 4.34, respectively. The mean percent morphine-release at 1 h dissolution after 30 min contact time was 2.00% (applesauce), 2.21% (apple juice), 3.00% (carrot puree), 3.73% (chocolate pudding), 2.02% (vanilla yogurt), 1.71% (chocolate pudding, pH 1.2), and 4.80% (chocolate pudding pH 7.5). The mean percent morphine-release at 1 h dissolution after 120 min contact time was 3.91% (applesauce), 4.39% (apple juice), 8.28% (carrot puree), 9.77% (chocolate pudding), 3.50% (vanilla yogurt), 2.76% (chocolate pudding, pH 1.2), and 16.12% (chocolate pudding pH 7.5). Texture analysis results showed the pellets sprinkled in different soft foods cracked with varying force and deformation distance. The cracks occurred under lower forces and with longer deformation distances when the pellets were sprinkled into higher pH soft food and had longer contact time with the soft food. Thermogravimetric analysis showed water content increased with higher pH of the soft food and longer contact time. For example, the water content was 0.26% for non-sprinkled pellets and 20.42% for pellets sprinkled in pH 7.5 PB for 120 min. The screening DOE results showed pH is the most dominant factor controlling drug release, followed by contact time and the interaction between pH and the contact time.

Conclusion: Pellets sprinkled over soft foods with higher pH and at 120 min contact time exhibited higher percent morphine dissolved at 1 h, lower mechanical strength and higher water content. Screening DOE showed that soft food pH, contact time and the interaction between the pH and contact time were the significant factors affecting the dissolution of the sprinkled pellets. The exploration of predictive modeling of the dissolution outcome from the cracking point and the water content is on-going.

References: [1] Cho, S.Y., et al., Prevalence and risk factors for dysphagia: a USA community study. Neurogastroenterology & Motility, 2015. 27(2): p. 212-219.
[2] Prasse, J.E. and G.E. Kikano, An Overview of Pediatric Dysphagia. Clinical Pediatrics, 2008. 48(3): p. 247-251.

Acknowledgments: Md Sohel Rana, Lorne Jordan and Kai-Wei Wu were supported in part by an appointment to the Oak Ridge Institute for Science and Education (ORISE) Research Participation Program at the Center for Drug Evaluation and Research administered by the ORISE through an agreement between the U. S. Department of Energy and CDER.
Disclaimer: The contents in this poster reflect the views of the authors and should not be construed to represent FDA’s views or policies. The mention of trades names, commercial products, or organizations is for clarification of the methods used and should not be interpreted as an endorsement of a product or manufacturer.