Stability Implications of Repackaging Paracetamol Tablets into Dose Administration Aids

Background: Despite the widespread use of dose administration aids (DAAs) there is little available data on the stability of drugs during repackaging or storage in these devices. Aim: To investigate the physicochemical stability of paracetamol tablets repackaged in DAAs. Method: Physicochemical stability studies were performed on a commonly used paracetamol tablet directly after heat-sealing in a DAA frequently employed in practice, then at ambient (25 oC; 60% relative humidity) and accelerated (40 oC; 75% relative humidity) conditions, over a 3-month period. Physical characteristics of the tablets (weight uniformity, physical appearance, thickness, hardness, friability, disintegration, dissolution rates) were evaluated at time = 0, directly after heatsealing, 1 month and 3 months. Chemical stability was confirmed by high performance liquid chromatography (HPLC). The results were compared to control samples stored in the original packaging at the various environmental conditions studied. Results: All compendial requirements for physicochemical stability were met for both ambient and accelerated conditions over the 3-month period. Chemical stability of paracetamol content fell within the required range of 95–105% of the labelled amount, for all environmental conditions. Conclusion: This study provides evidence on the stability of paracetamol tablets in a DAA, to support pharmacists in making sound clinical and operational decisions regarding the repackaging of paracetamol in these devices. J Pharm Pract Res 2006; 36: 25-8. INTRODUCTION Stability of a pharmaceutical may be defined as the capability of a particular formulation, in a specific container/closure system, to remain within its physical, chemical, microbiological, therapeutic and toxicological specifications.1,2 Pharmaceuticals are expected to meet their specifications for identity, purity, quality, and strength throughout their defined storage period at specific storage conditions. The stability of manufactured dosage forms is routinely confirmed by manufacturers, where stability studies on packaged dosage forms are conducted by means of real-time, long-term tests and accelerated stability tests at specific temperatures and relative humidities representing storage conditions experienced in the distribution chain of the climatic zone(s) of the country or region of the world concerned.3,4 Although stability of a dosage form is often seen to be the responsibility of the manufacturer, this does not include removal from the original packaging.5 In electing to repackage a drug into a dose administration aid (DAA) (medication compliance device/unit-dose container), pharmacists must consider the implications of the transfer to a non-manufacturer pack on drug stability. Despite the widespread use of these devices, there is little available data on the stability of the drugs during repackaging or storage in DAAs. The stability of a pharmaceutical is affected by many factors, such as the stability of the active ingredient(s), potential interaction between active(s) and excipients, manufacturing process, dosage form, packaging system, environmental conditions encountered during transport, storage and use, and length of time between manufacture and usage.1,3 In addition to the chemical decomposition (hydrolysis, oxidation, isomerisation, polymerisation, photochemical degradation) of the drugs and/or excipients, physical changes to the solid dosage form, such as changes in tablet hardness, friability, disintegration and/or the dissolution rate may lead to both altered physical appearance and/or bioavailability of the drug. Drug decomposition often does not follow simple reaction processes (kinetics) and with certain drug substances, more than one type of decomposition can occur simultaneously.6 Additionally, the kinetics of drug decomposition in solid dosage forms is often more complex than in solution.4,6,7 Any increase in temperature, often encountered in storage, transport or in-use, usually increases the rate of degradation. This situation is further complicated by the many different types of DAAs commercially available with varying degrees of protection against air, light and moisture and the many possible combinations of drugs being packed in a single blister/ sachet of a DAA with increased potential for interaction. It is therefore difficult to predict the physicochemical stability of drugs repackaged in DAAs without stability data on the specific drug in the DAA concerned. DAAs are commonly packed in a controlled room temperature environment (25 oC; 60% relative humidity — RH) however, they may be subsequently exposed to increased temperature and humidity in-use, especially in rural and remote regions of Australia, hence the need for studies at accelerated conditions (40 oC; 75% RH). Australia has climatic conditions encompassing the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Zones II, III and IV, where the long-term storage condition of 30 oC ± 2 oC/65% RH ± 5% RH (Zones III and IV) has been given as a suitable alternative to 25 oC ± 2 oC/60% RH ± 5% RH for Zones I and II.8 Additionally, paracetamol must be protected from moisture as it contains an amide group which is sensitive to hydrolytic degradation.6 This pilot study aimed to investigate the physicochemical stability of paracetamol tablets repackaged in DAAs. METHOD Physicochemical stability studies were performed on a commonly used paracetamol tablet (Panamax, Sanofi-