Process characterisation, optimisation and validation of production of diacetylmorphine/caffeine sachets: a design of experiments approach

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Abstract

Powder filled sachets containing a 3:1 (w/w) powder mixture of diacetylmorphine base and caffeine anhydrate were developed as a dosage form for smokable heroin used for the treatment of chronic, treatment-resistant heroin addicts. The powder mixture was filled into sachets using a micro dose auger filler machine. The goal of this study was to identify the most important process variables that influence precision of dosing. Five variables were tested: auger speed, agitator speed, hopper fill level, dose interval, and dose. An experimental design was used to study the effects of each of these variables, including possible non-linear and interaction effects. A 9-term regression model was constructed, explaining 94% of the observed variation in dose weight variation coefficient. Dose, agitator speed and hopper fill level were the most important variables. The regression model was used to identify optimal settings of the variables for four sachet doses intended for routine manufacture. The results of four test batches manufactured with these optimised settings showed that accurate (accuracy: 99.0–101.0%) and precise (CV: 3.2–5.3%) filling of diacetylmorphine/caffeine sachets is possible using the micro dose auger filler machine.

Introduction

In 1998, two clinical trials were initiated in the Netherlands to evaluate the effect of co-prescription of heroin (3,6-diacetylmorphine) and methadone on mental and physical health and social functioning of chronic treatment-resistant heroin dependent patients (Van den Brink et al., 2003). In The Netherlands, only 15–25% of the heroin addicts inject heroin, the remaining 75–85% inhale the heroin fumes that arise after heating heroin on aluminium foil until it evaporates (“chasing the dragon”; (Hendriks et al., 2001). Therefore, one of the two trials concerned co-prescription of inhalable heroin as the experimental intervention. As no pharmaceutical dosage form for inhalable heroin was available, it had to be developed specially for this trial. An important requirement was to avoid problems of patient non-compliance, by ensuring that the product could be used according to the long-established habits of the patients in the trial. A powder formulation was therefore preferred and a 3:1 (w/w) mixture of diacetylmorphine base and caffeine anhydrate was found to be a suitable basis for pharmaceutical smokable heroin. Diacetylmorphine base is more appropriate than diacetylmorphine hydrochloride, because it showed less degradation and larger recoveries after volatilisation (Huizer, 1987). Caffeine was added because it is commonly found in street heroin samples (Huizer et al., 1977, Kaa and Bent, 1986; de la Fuente et al., 1996, Risser et al., 2000) and because it has been shown to improve the volatilisation of diacetylmorphine (Huizer, 1987). Addition of excipients to alter the properties of the 3:1 (w/w) diacetylmorphine/caffeine powder mixture was considered undesirable, because of the possibility of adverse effects arising from volatilising and inhaling these substances. Therefore, four types of powder filled sachets were developed for the clinical trial, containing 75/25 mg, 100/33 mg, 150/50 mg, or 200/67 mg diacetylmorphine/caffeine (Klous et al., 2004). In the manufacturing process, a micro dose auger filler is used to fill the powder mixture into sachets. A long and narrow auger was designed specifically to accurately fill small amounts of powder by mechanically forced transport (ejection of several milligrams with each revolution of the auger). This principle of dosing is flexible with respect to dose, without the need to add excipients or alter excipient concentration in the powder mixture in order to obtain specific flow properties. The powder portions were packaged into sachets formed on-line from packaging foil, consisting of aluminium, paper, and polyethylene layers.

Powder filled sachets are not a common dosage form in the pharmaceutical industry, especially not for small doses (<1 g of powder). No literature was available on formulation issues in auger filling of powders. Furthermore, no scientific information could be found on the influence of process variables on accuracy and precision of dosing using a micro dose auger filler. It has become common practice, however, to identify important variables and subsequently optimise manufacturing processes using experimental design, especially when complex pharmaceutical processes are concerned. Granulation processes for example, have been studied extensively using design of experiments (DoE) (Voinovich et al., 1999, Badawy et al., 2000, Rambali et al., 2001, Paterakis et al., 2002). Response surface methodology (an effective tool in DoE to demonstrate interaction effects between factors) has been used to study many other complex formulation issues: tablet coating (Rege et al., 2002), preparation of nanoparticles (McCarron et al., 1999) or self-nanoemulsifying tablets (Nazzal et al., 2002), and drug release from controlled release formulations (Sanchez-Lafuente et al., 2002, Kramar et al., 2003).

Design of experiments and response surface methodology have therefore also been employed in this study. Our first goal was to identify important process variables that influence precision of diacetylmorphine/caffeine dosing by the micro dose auger filler machine. Our second goal was to optimise the manufacturing process for each of the four diacetylmorphine/caffeine dosages intended for routine production.

Section snippets

Materials

Diacetylmorphine base was obtained through the Central Committee on the Treatment of Heroin Addicts (Utrecht, The Netherlands) and caffeine anhydrate was purchased from Bufa (Uitgeest, The Netherlands). The formulation to be used in this validation experiment is a 3:1 (w/w) powder mixture of diacetylmorphine base and caffeine anhydrate. The powder mixture was prepared by mixing three parts of diacetylmorphine with one part of caffeine using a Model UM12 Stephan mixer (Stephan Electronic 2011,

Experiment design

All machine settings that were not dependent on properties of powder or hardware were included in the experiment design. This resulted in the five variables given in Table 1; ranges for the variables were selected on the basis of technical and practical limitations. For example, for D the technical limits were 0.05–50 mL (equalling 0.021–21 g diacetylmorphine powder mixture), but since our purpose for the machine was to fill quantities of 50–300 mg, this range was selected. For AuS, technical

Conclusion

The complex pharmaceutical manufacturing process of micro dose auger filling of diacetylmorphine/caffeine powder was successfully characterised using design of experiments. All parameters tested in the experiment design, but especially dose, agitator speed and hopper fill level were found to affect dosing precision either through linear, quadratic or interaction effects. A regression model was obtained that explained 94% of the observed variation in the dose weight CV. This model was used to

Acknowledgements

The authors would like to thank K. Ogbemichael, E. Vermeij, D. Meijer and the other pharmaceutical and analytical technicians involved for their work in manufacturing and quality control of the diacetylmorphine/caffeine sachets. This study was financially supported by the Netherlands Ministry of Health, Welfare and Sports through the Central Committee on the Treatment of Heroin Addicts (www.ccbh.nl).

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