title: Assessing impact of formulation and process variables on in-vitro performance of directly compressed abuse deterrent formulations.
abstract: Prescription drug products abuse/misuse is epidemic in United States. Opioids drug forms major portion of prescription drug product abuse. Abuse deterrence formulation (ADF) is one of the many approaches taken by sponsors to tackle this problem. It involves formulating opioids into dosage forms that will be difficult to abuse/misuse. Current investigation focused on evaluating the abuse deterrent properties (ADP) of ADF manufactured by direct compression method. Effect of process and formulation variables on ADP was investigated by statistical design of experiment (fractional factorial design). Independent factors studied were molecular weight of polyethylene oxide (Polyox™), curing time, temperature and method, and antioxidant type. Sotalol hydrochloride was selected as a model drug. ADP investigated were hardness/crush resistance, syringeability and injectability, physical manipulation (reduction into powder) and drug extraction in water and alcohol. Hardness and syringeability are evaluated by newly developed quantitative procedure. Other properties were also investigated such as morphology, crystallinity, assay and dissolution. The hardness and drug extraction was significantly (p<0.05) affected by curing temperature. Formulations could be powdered in 3 min irrespective of their hardness. Syringeability and injectability were intrinsic properties of the polymer used in the formulation, and were not affected by the investigated factors. Crystallinity of the polymer and drug changed, and was dependent upon curing temperature and time. The dissolution and assay were independent of formulation and process parameters studied. In conclusion, the study indicated some advantages of ADF product compared to non-ADF prepared by direct compression. However, the ADF should not be viewed as abuse proof product rather as incrementally improved product.
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Ziyaur
authors.initials: Z
authors.lastname: Rahman
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Korang-Yeboah
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Akhtar
authors.initials: A
authors.lastname: Siddiqui
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
authors.affiliation: Division of Product Quality and Research, Center for Drug Evaluation and Research, Food and Drug Administration, MD, USA; Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, USA. Electronic address: mkhan@pharmacy.tamhsc.edu.
authors.forename: Mansoor A
authors.initials: MA
authors.lastname: Khan
mesh_terms: D002626:Chemistry, Pharmaceutical; D004304:Dosage Forms; D004339:Drug Compounding; D006244:Hardness; D009293:Opioid-Related Disorders / Q000517:prevention & control*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011208:Powders; D012995:Solubility; D013015:Sotalol / Q000737:chemistry*
chemical_list: D004304:Dosage Forms; D011208:Powders; D011092:Polyethylene Glycols; D013015:Sotalol
keywords: Abuse deterrence; Crush resistance; Extraction; Hardness; Sotalol; Syringeability and injectability