Development and evaluation of solvent-free processing techniques for poorly water soluble drugs

Abstract

Drug development encompasses the entire process of bringing a new drug to the market and involves four stages: (1) drug discovery, (2) product development, (3) pre-clinical research and (4) clinical trials. Whereas for many decades, new active compounds were often identified via serendipity, nowadays high-throughput screening and combinatorial methods are applied. However, many of the found candidate drugs fail in clinical trial due to: adverse effects (10 %), toxicity (11 %), lack of efficiency (30 %) and poor bioavailability (30 %). Indeed, pharmaceutical industry witnesses a steady increase in poorly water-soluble drugs as lead compounds, i.e. 40 % of the drug molecules in development pipelines and 60 % of the drug molecules coming from chemical synthesis. This is of special concern for drug formulations intended for oral intake as good drug dissolution is a prerequisite for drug absorption and subsequently clinical response. Until now, comprehensive methods to predict oral absorption based on in vitro drug dissolution are limited, mainly due to the complexity of the processes in the gastro-intestinal tract and to complex pharmacokinetics. It became clear that to correlate in vitro drug dissolution and in vivo drug availability, one should consider drug dissolution and gastrointestinal permeability as fundamental parameters controlling the rate and extent of drug absorption. For this purpose, Amidon and co-workers proposed the Biopharmaceutical Classification System (BCS) scheme that sets the basis for in vitro-in vivo correlations between drug dissolution and drug absorption. Recent advances in drug formulation have introduced a variety of strategies to enhance the dissolution rate of poorly water-soluble drugs, and are therefore promising for the formulation of BCS class II drug molecules. These new techniques often use organic solvents to transform the drug into a high-energy amorphous state or to produce crystalline micro- and nanoparticles. However, a major drawback of using volatile organic solvents is residual traces in the final product that are hard to remove. These not only involve toxicity issues, but might also induce phase transformation over prolonged periods of storage, impairing stability of the drug formulation. In this regard, special guidelines have been issued by the European Pharmacopeia limiting the maximum allowed amount of residual solvents in pharmaceutical formulations Taking into account these considerations, this research explores, develops and evaluates several solvent-free processing techniques for poorly water-soluble drug. The initial approach to the drug-solubility issue involves formulating the poorly water-soluble drug carbamazepine into tablets, intended for oral intake, with a self-emulsifying excipient to increase drug dissolution. For this purpose, PEG-32 glyceryl laureate (Gelucire®44/14, Gattefossé, France) was chosen as previous work reporting on the use of Gelucire®44/14 as excipient in drug formulation highlighted its capability to enhance drug dissolution but also mentioned difficulties to formulate Gelucire 44/14 based formulations into immediate-release tablets for oral intake. Due to its low melting point and waxy behavior, Gelucire®44/14 acts as a binder, thereby strongly increasing the disintegration time of tablets produced via compression. In the pursuit of an immediate release tablet formulation, carbamazepine was first processed with Gelucire®44/14 via either granulation or spray drying and subsequently compressed into tablets. Compression was observed to strongly decrease drug dissolution, relative to the non-tableted granules and spray-dried powder. This could be attributed to the relatively long disintegration time of the tablets. To address this issue, super disintegrating excipients were added to the formulations. Unfortunately, these did not accelerate drug dissolution since no significant effect on tablet disintegration was observed. Likely this has to be attributed to the binding capacity of Gelucire®44/14. However, fast and complete tablet disintegration was obtained by incorporation of an effervescent mixture in the formulation. In this case tablet disintegration and full drug dissolution was reached within 15 min, thus presenting a suitable immediate release formulation for the poorly water-soluble drug carbamazepine. Further ahead we have focused on the formulation of drugs (i.e. itraconazole and febantel) with an even lower water-solubility for which the formulation approach, developed in Chapter 2, is insufficient. To formulate these drugs, we aimed to produce micro- and nanocrystalline suspensions containing Gelucire®44/14 as additional solubility enhancement agent. For this purpose, two top down and one bottom up approach were developed. The top down approaches involved either ball milling or ultrasound treatment, both in the presence of Gelucire®44/14, to reduce the size of existing drug crystals. Both techniques allowed to significantly reduce the size of the drug crystals, with ultrasound treatment being the most powerful method. Both methods also allow to enhance the dissolution of febantel with the ultrasound treated formulation providing the best dissolution. In case of itraconazole, no influence of both processing techniques was observed, which is likely to be attributed to its even lower water solubility. In the bottom up approach, itraconazole and febantel nanosuspensions were produced by dissolving the drug in molten Gelucire®44/14. This molten mixture was atomized into cold water. During the atomization, cavitation was induced by ultrasonication. This process yielded milky suspensions in the submicrometer range. Furthermore a fraction of the drug was found to be in amorphous state. The nanosuspensions of both drugs showed enhanced dissolution. In case of febantel drug dissolution was superior to the formulations produced via ball billing or sonication, while in case of itraconazole drug dissolution was obtained, which was not the case for any of the other formulations. In final stage an aqueous coacervation technique comprising a molten surfactant/drug mixture with febantel as model drug was developed in view of large scale drink water medication for veterinary purposes. This drug is widely use in animal large scale medication and its primary way of administration is through drinking water. Its low solubility together with everyday application in veterinary practice made it the ideal candidate for the development of a new solubilization technique based on the preparation of a highly loaded drug coacervate phase by using polyethoxylated castor oil (Cremophor®EL, BASF). In a first step in the melt-coacervation approach, febantel was dissolved in liquid micelle-forming surfactant (i.e. Cremophor®EL) under heating. Next, the liquid was added to an aqueous maltodextrin solution under high shear homogenization. Spontaneously, a coacervate is formed, comprising a maltodextrin rich phase and a Cremophor®EL rich micellar phase, with the febantel being distributed within the hydrophobic core of the Cremophor®EL micelles. This phenomenon is due to the incompatibility between concentrated aqueous solutions of maltodextrin and Cremophor®EL. Further processing via spray drying yielded a dry powder as the excess of maltodextrin was able absorb the liquid Cremophor®EL phase. Alternatively, a dry formulation could also be obtained by granulation of the Cremophor EL rich phase as granulation liquid and tapioca dextrin as solid carrier. Importantly, X-ray diffraction elucidated that both techniques allowed retaining febantel in amorphous state. Drug dissolution was found to be fast and complete, with the spray dried formulation performing the best. The spray-dried formulation showed long-term stability and could provide constant drug levels in a drinking water system, whereas large drug fluctuations were observed for the commercial Rintal formulation. Preliminary in vivo studies in pigs, further demonstrated the potential of the melt-coacervation technique. Summarizing, this work explores several solvent-free approaches to enhance the dissolution of poorly water-soluble drugs. For this purpose it was found essential to use bio-compatible surface-active agents and to reduce the particle size of the drug crystals. Especially the formation of drug crystals in the nano-range was found to be a potent strategy to enhance drug dissolution