Prochlorperazine tablets repackaged into dose administration aids: can the patient be assured of quality?

Transcription

1 Journal of Clinical Pharmacy and Therapeutics (2009) 34, doi: /j x ORIGINAL ARTICLE Prochlorperazine tablets repackaged into dose administration aids: can the patient be assured of quality? B. Glass* BSc Hons BTech-Hons (Marketing) BPharm PhD, M.Mangan*BSc BEd MEd and A. Haywood BPharm PhD *School of Pharmacy and Molecular Sciences, James Cook University, Townsville, Qld and School of Pharmacy, Griffith University, Gold Coast Campus, Qld, Australia SUMMARY Background and objective: Patients are increasingly requiring their medications to be repackaged into dose administration aids because of the positive outcomes associated with reduction in medication related hospitalization and adverse effects due to improved medicines management. Since the stability of these repackaged medications is not the responsibility of manufacturer, it is important that drug substances with potential stability issues be identified. Thus the objective of this study was to evaluate the stability of prochlorperazine, a light sensitive drug repackaged into dose administration aids (DAAs), in order to provide guidelines to the pharmacist and advice to the patient on appropriate storage. Methods: Prochlorperazine tablets were stored repackaged in DAAs and in their original packaging for 8 weeks at ambient (25 ± 1 C; 60 ± 1Æ5% RH), accelerated (40 ± 1 C; 75 ± 1Æ5% RH) and in-use conditions encountered in situ both in a pharmacy and the patients home. They were assessed for both chemical (using a validated HPLC method) and physical stability according to British Pharmacopoeial (BP) standards. In addition, photostability testing was undertaken under ICH conditions. Results and discussion: Chemical and physical stability was confirmed to be within BP Limits. There were, however, noticeable organoleptic changes in the tablets stored under in-use conditions with a progressive grey discolouration over the 8 weeks, starting in week 2. Received 18 December 2007, Accepted 16 August 2008 Correspondence: B. Glass, Chair of Pharmacy, School of Pharmacy and Molecular Sciences, James Cook University, Douglas Campus, Townsville, Qld 4811, Australia. Tel.: ; fax: ; beverley.glass@jcu.edu.au Conclusion: Despite the confirmation of physical and chemical stability within BP limits, the discoloration and the potential for photodegradants to cause adverse effects in patients must lead us to draw the conclusion that the quality of this medication has been compromised. Pharmacists thus need to take this into account in repackaging and storage of prochlorperazine in DAAs and advise patients to store their DAA protected from light, heat and humidity. Keywords: dose administration aids, prochlorperazine, quality, repackaging, stability INTRODUCTION An increasing number of patients are receiving their medication in multi-compartment compliance (MCCAs) or dose administration aids (DAAs) due to the benefits in terms of health outcomes and cost of health care. The Australian Government Department of Health and Ageing has funded a number of professional programs and services under the Better Community Health Initiative of the 4th Community Pharmacy Agreement, including the Dose Administration Aids (DAA) Program (1). The objective of the DAA program is to identify patients who most benefit from the supply of a DAA, to develop a sustainable service and payment model capable of meeting the program s aim and to trial the broader use within the community setting. The provision of a DAA service through community pharmacies is expected to reduce medication-related hospitalization and adverse events through improved medication management. This should result in improved quality of life and health status for patients and have flow on benefits for the community by reducing the demand on aged Ó 2008 James Cook University Ó 2008 Blackwell Publishing Ltd 161

2 162 B. Glass et al. care facilities and costs associated with adverse reactions to medication mismanagement (1). Despite the widespread use of these devices, there is little available data on the stability of the drug products when repackaged into such devices (2 5). A recent survey of 392 products revealed that, although some information can be obtained from manufacturers, there is still a shortage of short-term stability data for the transfer of drug products into these devices (2). The stability of manufactured dosage forms is routinely confirmed by the manufacturer as per regulatory requirements (6), 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 humidity s representing storage conditions experienced in the distribution chain of the climatic zone(s) of the country or region of the world concerned. Manufacturers packaging is designed to protect drug products from environmental factors encountered during storage, such as light, air (oxygen, carbon dioxide, other gases) and moisture while ensuring limited interactions between the product and the packaging material. However, this does not guarantee the stability of the active pharmaceutical ingredient (API) and the drug product on removal and repackaging into a DAA. Although the stability of a dosage form is often seen to be the responsibility of the manufacturer, this does not include removal from the original packaging. In electing to repackage a drug product into a DAA, pharmacists must consider the implications on drug stability of the transfer to a nonmanufacturer pack. The shelf-life of a drug product may be affected by the intrinsic stability of the active pharmaceutical ingredient (API) and interactions between the API and the excipients. Instability can lead to (i) loss of potency due to the degradation of the API, (ii) accumulation of potentially toxic degradation products causing adverse reactions in patients and (iii) changes in the physical appearance of a product that may affect patient compliance through loss of confidence in the medication. In addition to chemical decomposition by hydrolysis, oxidation, isomerization, polymerization or photochemical degradation of the API and or excipients, physical changes in tablet hardness, friability, disintegration or dissolution rate may lead to altered bioavailability and thus therapeutic efficacy of the drug product. Prochlorperazine, a member of the piperazine subclass of phenothiazines, widely used as an antiemetic is susceptible to oxidation to the sulphoxide (metabolite and photodegradant) under the influence of light. These main metabolites and degradants of all phenothiazines are found to be inactive at the dopamine receptors. Prochlorperazine causes photosensitivity effects in patients attributed to dechlorination at C2 with the release of HCl (7, 8). Since prochlorperazine has been identified as one of those medicines frequently repackaged into DAAs in Australia (1), this study aimed to investigate its physicochemical stability under various storage conditions, in order to determine whether the patient can assured of quality on repackaging. METHODS Sample preparation Physicochemical stability studies were performed on 5 mg prochlorperazine tablets (Stemetil Ò ; Sanofi- Aventis, Sydney, NSW, Australia) repackaged into a DAA frequently employed in practice (Multi-Dose Webster-Pak Ò ; Webstercare, Leichardt, NSW, Australia), over a period of 8 weeks. Physical characteristics of the tablets, namely; tablet weight uniformity, physical appearance, hardness, friability, disintegration and dissolution rates, were evaluated according to British Pharmacopoeia (BP) compendial requirements, at the following intervals: time = 0 weeks, 4 weeks and 8 weeks. Chemical stability was confirmed by high performance liquid chromatography (HPLC). Photostability studies were performed as per the International Committee on Harmonization (ICH) guidelines and the amount of prochlorperazine quantitated by the validated HPLC method. The results were compared to control samples stored in the original blister packaging at the various environmental conditions. All samples had a remaining shelf-life of at least 2 years at the time of sampling. All tablets were chosen at random from the respective packaging (DAA or control) for the physicochemical stability tests described below. Percentage relative standard deviation and standard error of the mean were determined for representation of accuracy in the measurement. Statistical package for the Social

3 Stability of prochlorperazine tablets in DAAs 163 Sciences was used for ANOVA analysis to determine the level of significance of the results obtained. Results with P < 0Æ05 were considered statistically significant. Storage conditions Prochlorperazine tablets were stored repackaged in DAAs and in their original packaging, over a period usually encountered in practice (8 weeks) (9). Storage conditions included controlled room temperature (25 ± 1 C; 60 ± 1Æ5% RH) and accelerated (40 ± 1 C; 75 ± 1Æ5% RH) conditions in an ICHcompliant climatic chamber (Binder KBF 720; Binder, Great River, NY, USA) as per ICH guidelines (6). A third storage condition was chosen to simulate in-use conditions encountered in situ (i.e. during storage in pharmacies from time of repackaging to dispensing and in patients homes) where tablets were placed blister-side up on a bench top (150 cm from the light source) exposed to fluorescent lighting (OSRAM L36W Lumiluxpluseco; Cool White, Pennant Hills, NSW, Australia) and indoor indirect daylight for 12 h per day at 25 ± 2 C. Physical stability Appearance was determined organoleptically by comparison to the original samples. Tablet weight uniformity was determined on twenty tablets using an AND HM-200 analytical balance in accordance with Ph. Eur. method 2Æ9Æ5 (10). Tablet friability was determined on 20 tablets using a Vankel dual drum friabilator (Varian, Cary, NC, USA) in accordance with Ph. Eur. method 2Æ9Æ7 (11). Tablet hardness and thickness was determined on 20 tablets using a Vankel VK 200 tester using the standard testing protocol in accordance with Ph. Eur. method 2Æ9Æ8 (12). Disintegration was determined on six tablets using a Vankel (Varian) disintegration tester in accordance with Ph. Eur. method 2Æ9Æ1, using Apparatus A (13). A disc was added to each tube and purified water (Millipore ELIX10 electrodeionization system) (37 ± 0Æ5 C) was used as the medium. Dissolution tests were performed on six tablets as per Ph. Eur. method 2Æ9Æ3 (14), on a BP Apparatus II (paddle apparatus) (Vankel, VK 7000; Varian) operating at 75 g, using 0Æ1 M hydrochloric acid (Sigma Aldrich) dissolution media (500 ml) maintained at 37 ± 0Æ5 C. Filtered (0Æ45 lm, Millipore) samples were assayed on a Cary 100 UV VIS spectrophotometer (Melbourne, Vic., Australia) with multicell holder at 254 nm at 2-minute intervals over a period of 60 min as per the USP (United States Pharmacopoeia) monograph for prochlorperazine tablets (15), since no test for dissolution is described in the current BP monograph for prochlorperazine tablets (16). The BP compendial requirements for the above physical tests are as follows: Uniformity of weight: Not more than two of the individual masses, of twenty units taken at random, deviate from the average mass by more than 7Æ5% (i.e. for a tablet of greater than 80 mg and less than 250 mg average mass) and none deviates by more than twice that percentage (10). Friability of uncoated tablets: A maximum loss of 1% of the mass of the tablets tested is considered to be acceptable. For tablets weighing up to 0Æ65 g each, a sample of 20 tablets is taken (11). Tablet hardness: Tablets are oriented in the same way with respect to the direction of application of the force, and results are expressed, in newtons (N), as the mean, minimum and maximum values of the forces measured (12). Disintegration: Uncoated tablets comply with the test for disintegration of tablets and capsules described in Ph. Eur. method 2Æ9Æ1 (13). The tablets comply with the test if all six have disintegrated after 15 min as per Ph. Eur. monograph 0478 (17). Dissolution: For each of the six tablets tested, the amount of active ingredient in the solution after 60 min is not less than 75% of the labelled amount (15). Chemical stability A stability-indicating HPLC method, adapted from the USP method for prochlorperazine maleate tablets (15) was utilized to quantify prochlorperazine in the presence of its degradants and formulation excipients. The Varian ProStar Ò system consisted of a 240 solvent delivery module, 210 autosampler and a 330 photodiode array detector. The stationary phase was a Pursuit XRs C18 (5 lm, 250 4Æ60 mm) reverse-phase column (maintained at 40 C) and an octane sulphonic acid: acetonitrile: acetic acid 1% (Sigma Aldrich; Castle Hill, NSW, Australia) (25 : 65 : 10) mobile phase and a detection wavelength of 254 nm was used. The flow rate

4 164 B. Glass et al. was 1Æ0 ±0Æ1 ml min with an injection volume of 25 ll using a 100 ll fixed loop. A calibration curve for prochlorperazine was constructed from 2 lg ml to 8 lg ml (r 2 =0Æ999). Prochlorperazine assay: Triplicate samples were prepared by accurately weighing 20 tablets for each of the storage conditions. The finely crushed powder was mixed and diluted appropriately with mobile phase and filtered through a 0Æ45 lm filter (Millipore Ò ; Bedford, MA, USA) to prepare a solution containing approximately 4 lg ml prochlorperazine (15). Content uniformity: Each of 10 tablets was mixed and diluted appropriately with mobile phase to prepare a solution containing approximately 4 lg ml prochlorperazine, as per Ph. Eur. method 2Æ9Æ6 (10). All samples were protected from light prior to and during analysis. Photostability DAAs were placed blister-side up in the Hereaus Suntest CPS+ (ATLAS, Geldhausen, Germany) and exposed to the visible wavelength nm at 1Æ2 million lux hours and the UV wavelength nm at 200 watt hours m 2 as per the ICH guidelines (18). Protected samples (wrapped in aluminium foil) were used as dark controls to determine the effect of temperature. Triplicate samples were prepared by accurately weighing 20 tablets for each of the test conditions. The amount of prochlorperazine was quantitated as per the HPLC method described above. RESULTS Physical stability The effect of various storage conditions on the physical stability of the prochlorperazine tablets repackaged in the DAA and original blister packaging (control) is shown in Table 1. Dissolution rate profiles of the prochlorperazine tablets stored under various storage conditions in the DAA and original packaging (control) are shown in Fig. 1. The BP compendial requirements for weight uniformity, friability, hardness, disintegration and dissolution were met for both the samples (i.e. tablets stored in the DAA) and controls (i.e. tablets stored in the original blister packaging), stored under controlled room temperature (25 C; 60% RH), accelerated (40 C; 75% RH) and in-use conditions, over the period of 8 weeks. The average weight at each sampling period, under all storage conditions, showed no trends in weight loss or gain, demonstrating no significant moisture sorption or desorption. No significant difference (P >0Æ05) in physical properties between the samples and controls for each storage condition was observed. Therefore, quality of the prochlorperazine tablets was confirmed regarding their disintegration, hardness, weight uniformity, friability, appearance and dissolution rate over the period of 8 weeks with all results falling within the compendial requirements (Table 1), as detailed under methods. There were, however, noticeable organoleptic changes in the tablets stored under in-use conditions with a progressive grey discolouration over the 8 weeks, starting in week 2. The prochlorperazine tablets stored under controlled room temperature (25 C; 60% RH) and accelerated (40 C; 75% RH) conditions did not change from their original, pure white colour, attributed to their storage inside a dark climatic chamber. Chemical stability Method validation for specificity, linearity, accuracy and precision was carried out as per the ICH guidelines (19). The retention time for prochlorperazine was 4Æ2 min with peak purity determined through spectral library comparison and peak purity determinations (Varian Prostar Polyview 2000) of the respective samples and standard solutions. The absence of co-eluting degradants and excipients was verified with spectral similarities of >0Æ999 achieved (photodiode array detection) for the pure and sample prochlorperazine peaks. Specificity is thus confirmed and illustrated in representative HPLC chromatograms showing the separation of degradants from prochlorperazine (Fig. 2). Linearity was confirmed over the concentration range used (r 2 =0Æ999). Accuracy was conducted using nine determinations over three concentrations covering the range and resulted in an average recovery of 100Æ09%, while precision after six determinations at 100% of the concentration resulted in a average % RSD of 0Æ91. Stability of the samples assayed was

5 Table 1. Effect of various storage conditions on the physical stability of prochlorperazine tablets Physical test Requirement Storage condition Packaging Results Friability a (% loss) Max loss of 1% of the t =0 0Æ12 tablets mass is acceptable. Week 4 25 C 60% RH Webster-pak 0Æ02 25 C 60% RH Original 0Æ09 40 C 75% RH Webster-pak 0Æ18 40 C 75% RH Original 0Æ11 In-use Webster-pak 0Æ08 In-use Original 0Æ10 Week 8 25 C 60% RH Webster-pak 0Æ10 25 C 60% RH Original 0Æ19 40 C 75% RH Webster-pak 0Æ24 40 C 75% RH Original 0Æ16 In-use Webster-pak 0Æ16 In-use Original 0Æ12 Hardness b (N) t =0 27Æ51 ± 3Æ49 Week 4 25 C 60% RH Webster-pak 28Æ15 ± 4Æ86 25 C 60% RH Original 29Æ62 ± 3Æ79 40 C 75% RH Webster-pak 17Æ16 ± 2Æ75 40 C 75% RH Original 23Æ78 ± 4Æ60 In-use Webster-pak 24Æ32 ± 3Æ99 In-use Original 30Æ06 ± 4Æ21 Week 8 25 C 60% RH Webster-pak 29Æ08 ± 4Æ05 25 C 60% RH Original 31Æ58 ± 3Æ61 40 C 75% RH Webster-pak 21Æ57 ± 4Æ07 40 C 75% RH Original 23Æ78 ± 3Æ63 In-use Webster-pak 18Æ44 ± 2Æ58 In-use Original 27Æ36 ± 3Æ51 Weight uniformity b Disintegration c (seconds) <Two of the individual masses deviate from the average mass by >7Æ5% All tablets disintegrate after 15 min Stability of prochlorperazine tablets in DAAs 165 t =0 0Æ1389 ± 0Æ003 Week 4 25 C 60% RH Webster-pak 0Æ1407 ± 0Æ C 60% RH Original 0Æ1408 ± 0Æ C 75% RH Webster-pak 0Æ1399 ± 0Æ C 75% RH Original 0Æ1414 ± 0Æ003 In-use Webster-pak 0Æ1417 ± 0Æ003 In-use Original 0Æ1417 ± 0Æ003 Week 8 25 C 60% RH Webster-pak 0Æ1400 ± 0Æ C 60% RH Original 0Æ1405 ± 0Æ C 75% RH Webster-pak 0Æ1423 ± 0Æ C 75% RH Original 0Æ1414 ± 0Æ003 In-use Webster-pak 0Æ1413 ± 0Æ002 In-use Original 0Æ1414 ± 0Æ003 t =0 25 Week 4 25 C 60% RH Webster-pak C 60% RH Original C 75% RH Webster-pak C 75% RH Original 20 In-use Webster-pak 20 In-use Original 25 Week 8 25 C 60% RH Webster-pak C 60% RH Original C 75% RH Webster-pak C 75% RH Original 14 In-use Webster-pak 16 In-use Original 18

6 166 B. Glass et al. Table 1. Continued Physical test Requirement Storage condition Packaging Results Dissolution d (% dissolved) >75% remaining after 60 min t =0 97Æ4 ±1Æ2 Week 4 25 C 60% RH Webster-pak 93Æ8 ± 1Æ4 25 C 60% RH Original 95Æ8 ± 1Æ8 40 C 75% RH Webster-pak 99Æ8 ± 1Æ3 40 C 75% RH Original 98Æ3 ± 1Æ9 In-use Webster-pak 99Æ3 ±2Æ7 In-use Original 102Æ0 ±2Æ3 Week 8 25 C 60% RH Webster-pak 101Æ2 ± 1Æ8 25 C 60% RH Original 101Æ3 ± 2Æ3 40 C 75% RH Webster-pak 99Æ0 ± 1Æ6 40 C 75% RH Original 98Æ9 ± 2Æ2 In-use Webster-pak 99Æ9 ±1Æ8 In-use Original 97Æ8 ±1Æ1 RH, relative humidity. a Values expressed as % mass loss (n = 20). b Values expressed as mean ± SD (n = 20). c Values expressed in seconds (n = 6). d Values expressed as mean ± SD (n = 6). % dissolution t = 0 In-use at 8 weeks In-use (control) at 8 weeks 25ºC 60%RH at 8 weeks 25ºC 60%RH (control) at 8 weeks 40ºC 75%RH at 8 weeks 40ºC 75%RH (control) at 8 weeks Time (min) Fig. 1. Dissolution rate profiles of prochlorperazine tablets stored under various conditions. confirmed for 6 h with a % RSD of 0Æ75. Concentrations of prochlorperazine in the samples were determined from respective peak areas in relation to constructed standard curves and then converted to a percentage of the initial prochlorperazine concentration. Representative HPLC chromatograms showing the separation of degradants from prochlorperazine are shown in Fig. 2. Prochlorperazine assay: The amount of prochlorperazine per tablet (vs. labelled amount) as a function of storage time is shown in Table 2. The results showed that the prochlorperazine content was within the range (92Æ5% 107Æ5% of labelled amount) specified in the BP monograph for prochlorperazine tablets (16) under all storage conditions over the period of 8 weeks. Content uniformity: The individual prochlorperazine content for each of the 10 tablets stored in the DAA and original packaging was between 85% and 115% of the average content as per Ph. Eur. method 2Æ9Æ6 (10) for each of the storage conditions (Table 2). The BP compendial requirements for prochlorperazine content (i.e. assay) (16) and formulation consistency (i.e. content uniformity) (10) were met for both the samples (i.e. tablets stored in the DAA) and controls (i.e. tablets stored in the original blister packaging), stored under controlled room temperature (25 C; 60% RH), accelerated (40 C; 75% RH) and in-use conditions, over the period of 8 weeks. No significant difference (P > 0Æ05) between the samples and controls for each storage condition was observed. Photostability Irradiation under the ICH conditions resulted in 104Æ32% and 104Æ87% of prochlorperazine remaining for the UV and visible light tests respectively, while 104Æ57% prochlorperazine was reported for the dark control. The results therefore show that the prochlorperazine content was within

7 Stability of prochlorperazine tablets in DAAs 167 Fig. 2. Representative HPLC chromatograms showing (a) prochlorperazine reference standard, (b) prochlorperazine tablets, (c) separation of degradants from prochlorperazine tablets after forced degradation by light and (d) forced degradation of prochlorperazine by oxidation (H 2 O 2 ). the range of 92Æ5 107Æ5% of the labelled amount. This confirms that there is no degradation occurring due to exposure to light (Hereaus Suntest CPS+ was maintained at 40 C). A change in colour to a pale grey to beige was observed for the samples exposed to light and not the dark controls. DISCUSSION A recent study (9) examined the stability implications of repackaging a commonly used paracetamol (a) (b) (c) (d) tablet in a DAA. Paracetamol has the potential to undergo hydrolysis and therefore requires protection from moisture. The samples in this study were stored under controlled laboratory conditions (i.e. long-term and accelerated) as per ICH guidelines (6), for a 3-month period. The results of the stability study were extrapolated to suggest that paracetamol tablets repackaged into a DAA offering sufficient protection from moisture would remain stable for a reasonable in-use period of approximately 6 weeks (i.e. allowing 2 weeks for advanced packing and delivery on a 4-week supply). Another study investigated the in-use stability implications of repackaging a light-sensitive medication into commonly used DAA over a conventional in-use time period of 8 weeks (20). Storage conditions were chosen to reflect those typically encountered in a patient s home ( Home-conditions ) and in a pharmacy offering a repackaging service ( Pharmacy-conditions ). The stability studies revealed that the tablets stored under Control-conditions and Home-conditions complied with the compendial requirements for hardness, friability, weight uniformity, dissolution and disintegration and also remained within the specified limits of furosemide content. The tablets stored under Pharmacy-conditions met the compendial requirements, however, displayed a progressive yellow discolouration over the 8-week storage period, attributed to exposure to fluorescent lighting not commonly encountered in the Home-conditions. Although the colour change was noted as having negligible effects on the furosemide content and physicochemical parameters of the tablets, it was considered an unacceptable change, since patients are likely to be concerned about a possible compromise in the quality of the medication, and this may have an effect on patient acceptance and hence compliance. CONCLUSION This study has shown that prochlorperazine tablets repackaged into a DAA will remain stable for a reasonable in-use period of 8 weeks (i.e. allowing for approximately 2 weeks for advanced packing and delivery on a 4-week supply). Many different types of DAAs are commercially available, offering varying degrees of protection against air, light and moisture. The DAA used in this study has been

8 168 B. Glass et al. Table 2. Effect of various storage conditions on the chemical stability of prochlorperazine tablets Chemical test Requirement Storage condition Packaging Results Assay a Content uniformity b Content is within 92Æ5% 107Æ5%of the labelled amount Individual 104Æ3 ±2Æ1 85% 115% of the average content t = 0 103Æ3 ±0Æ3 Week 4 25 C 60% RH Webster-pak 102Æ6 ± 2Æ3 25 C 60% RH Original 106Æ8 ± 1Æ5 40 C 75% RH Webster-pak 104Æ8 ± 0Æ5 40 C 75% RH Original 105Æ9 ± 0Æ1 In-use Webster-pak 103Æ1 ±0Æ8 In-use Original 104Æ3 ±0Æ3 Week 8 25 C 60% RH Webster-pak 104Æ3 ± 0Æ9 25 C 60% RH Original 106Æ0 ± 0Æ6 40 C 75% RH Webster-pak 103Æ5 ± 1Æ8 40 C 75% RH Original 103Æ2 ± 1Æ2 In-use Webster-pak 101Æ3 ±1Æ5 In-use Original 101Æ7 ±1Æ7 t = 0 103Æ2 ±1Æ1 Week 4 25 C 60% RH Webster-pak 104Æ3 ± 2Æ1 25 C 60% RH Original 106Æ1 ± 3Æ4 40 C 75% RH Webster-pak 103Æ6 ± 2Æ8 40 C 75% RH Original 104Æ4 ± 2Æ5 In-use Webster-pak 104Æ2 ±2Æ5 In-use Original 102Æ5 ±3Æ1 Week 8 25 C 60% RH Webster-pak 104Æ8 ± 2Æ4 25 C 60% RH Original 104Æ3 ± 2Æ6 40 C 75% RH Webster-pak 101Æ6 ± 2Æ3 40 C 75% RH Original 103Æ3 ± 2Æ9 In-use Webster-pak 103Æ2 ±2Æ1 In-use Original 103Æ0 ±2Æ4 RH, relative humidity. a Values expressed as mean ± SD (n = 3). b Values expressed as mean ± SD (n = 10). identified as one of the most commonly used in practice and offers sufficient protection against moisture. However, due to the discolouration of prochlorperazine tablets after 2 weeks, DAAs should be protected from light immediately after repackaging in the pharmacy and patients should be advised to store DAAs in a cool, dark place. The following practical recommendations for ensuring the stability of medication repackaged in DAAs, arising from this study and others (9, 20) include; firstly, protecting the DAA containing drugs susceptible to photodegradation from light in the pharmacy and in patients homes, achieved by either placing the DAA into a light-protecting sleeve (e.g. foil, cardboard) and or storing the DAA protected from light; secondly, careful removal of tablets to prevent accidental rupture of adjacent blisters, thus exposing tablets to air and moisture; thirdly, monitoring the DAA integrity during repackaging, dispensing and throughout the in-use period; and fourthly, consideration of an appropriate location to store the DAA to avoid unnecessary exposure to light, heat and humidity. The results of this study provide further evidence to support pharmacists in making decisions regarding the repackaging to assure the patient of the quality of these medications in DAAs. ACKNOWLEDGEMENTS The authors wish to acknowledge the financial support of James Cook University in Townsville and Griffith University on the Gold Coast in Australia and the technical assistance of Mrs Juliana Emmerson of Pharmacy at James Cook University in Townsville, Australia.

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