In fact, it is estimated that up to 80% of new small molecule drugs in development can be regarded as poorly soluble. Pharmaceutical scientists are therefore often under pressure to improve the solubility of these challenging compounds in order to maximize exposure and reduce variability.
There are several techniques that are commonly used to improve the dissolution of drug compounds in aqueous media. These include:
If the drug substance is a weak acid or weak base then it may be possible to form a salt with a suitable counter ion. Salts are often more water-soluble than the free acid or free-base form of the compound. This approach is not appropriate for neutral molecules. Also, there is no guarantee that the water-solubility of the salt will be markedly greater than the free form of the drug.
If drug uptake into the body is considered to be dissolution rate limited2 then reducing the particle size and hence increasing the surface area to increase dissolution rate can have a significant influence on rate and extent of absorption. However, where a high dose is required—as is the case for many anti-viral and oncology drugs—or if aqueous solubility is particularly low then particle size reduction will have a limited effect on drug uptake, even with nano-sized particles.
Solubility-enabling formulation technologies
Several formulation strategies can be considered for enhancing the water-solubility of compounds. The preparation of a drug-cyclodextrin inclusion complex is a common approach to improving solubility of a drug and is frequently used for pre-clinical animal pharmacokinetic studies. It is not unusual to require high concentrations of cyclodextrin in solution to achieve satisfactory drug solubility, which can be impractical for administering higher drug loadings.
Another solubility-enhancing strategy is the use of lipid-based or self-emulsifying vehicles, which can be presented in capsule form. This can be a particularly effective strategy for highly lipophilic drugs. However, the quantity of drug, which can be dissolved in a lipid or self-emulsifying vehicle is often quite limited.
The use of solid dispersions for enhancing drug solubility has become a popular strategy in recent years because of its applicability to a wide range of drug types and dosing requirements. There are several types of solid dispersion that have been used for pharmaceutical purposes, as summarized in Table 1. In the majority of cases formulation scientists aim to produce a single-phase glass solution or solid solution, where the drug is molecularly dispersed within the matrix. The term amorphous solid dispersion (ASD) is often used in the scientific literature to refer to a single-phase solid solution.
The mechanism by which ASDs are able to enhance the aqueous solubility of poorly soluble compounds is not fully understood, though the spring and parachute model3 is often used to describe how solid dispersions achieve supersaturation of a drug on dispersion in aqueous fluids. It is however accepted that chemical affinity between drug and polymer is important both for maintaining the amorphous state and for drug solubility enhancement.
Polymer selection is therefore a critical aspect in the development of ASD formulations. To assess the practicality of producing an ASD it is necessary to screen a selected range of polymers with increasing drug loadings on a small scale. A film casting approach4 is generally used for generation of test samples. These samples are checked for amorphicity using techniques such as optical microscopy, x-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). The film-cast samples are then subjected to stressed storage conditions before re-examination to determine their physical state. Those samples, which remain amorphous are considered for further formulation development. The polymers, which are used in solid dispersion formulations are largely limited to those which are established pharmaceutical excipients. Examples of polymers used in solid dispersions are hydroxypropylmethyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), hydroxypropylmethyl cellulose acetate succinate (HPMC-AS) and poly vinylpyrrolidone/vinyl acetate co-polymer.
Producing solid dispersions on a small scale as a screening exercise can be well controlled by those with experience in these techniques, but what about the practicality of scale-up for manufacture of clinical trials materials, or commercial-scale products? The processes, which have been generally adopted for producing solid dispersions are spray-drying and hot melt extrusion, both of which are scalable and are now well established in the pharmaceutical industry. Spray drying is the most universally applicable process for a wide range of drug substances, including those with fragile chemistries (e.g. thermo-labile compounds, enzymes, etc.).
The process requires the dissolution of the drug and polymer in a suitable solvent (usually organic solvent) and then spraying the solution in a hot gas stream into an evaporation chamber, resulting in the precipitation of drug/polymer particles. Bench-scale spray-dryers are capable of producing a few grams of material up to typically 1 -2 kg. Pilot-scale to commercial scale spray-dryers can produce 10s to 100s of kilos of product. The material recovered from the spray-dryer often has poor powder flow characteristics and most likely will require additional processing in order to provide a suitable end product. Spray-dried intermediates are therefore generally pre-compressed with a ‘densifying’ bulking agent using roller compaction to produce granular material more suited for encapsulation or tableting.
Hot melt extrusion (HME) is a more cost efficient and environmentally friendly process compared with spray-drying (no solvents involved). It involves feeding the drug and polymer into a heated screw-fed barrel, whereby the polymer and drug melt and mix together in the barrel producing a co-melt. On exit from the extruder the molten extrudate solidifies on cooling and can then be chopped/milled into granules for filling into capsules or further processing into tablets.
Not all drugs are suited to HME. The drug substance must be able to withstand the processing conditions within the extruder and be able to form a homogenous melt with the polymer carrier within the processing temperature range of the polymer. The smallest of the extruders can produce 20 g/hour up to 2 kg/hour whereas the largest extruders can produce greater than 50 kg/hour.
Although amorphous solid dispersions to an extent are still considered non-conventional, there are now many commercial pharmaceutical products, which are based on solid dispersion technologies, some examples of which are provided in Table 2. The trend in the number of solid dispersion based products being approved continues to increase year on year (Figure 1), which is certainly linked to the increase in poorly soluble compounds in development pipelines but can also be attributed to a greater understanding and confidence in the use of these systems and in particular our ability to determine drug-polymer miscibility and prediction of amorphous stability.
Indeed, it is the thermodynamic instability of amorphous systems, which presents us with the most significant challenge. How can we be certain that the amorphous drug will not crystallize over the shelf life of the product, resulting in slower or incomplete dissolution? This question continues to haunt those developing formulations based on solid dispersion technologies. At present, stressing samples by storage at high temperature and humidity is the standard approach to predicting physical stability of solid dispersions.
However, stability prediction based on theoretical modeling is a buoyant area of research. The use of Flory-Huggins crystal lattice theory for predicting drug solubility in polymer carriers underpins the work of many research groups5 and there is much progress being made in this field, though there is still a great deal to accomplish before modeling becomes a reliable tool for stability prediction purposes.
In summary, can the use of solid dispersion technology be considered a universal approach for all poorly water-soluble compounds? The answer is that none of the strategies used for enhancing drug dissolution in aqueous media are suited to all drugs and all dosing requirements, including solid dispersions. Predicting the stability of the amorphous state for solid dispersions continues to be an issue, which keeps formulators awake at night and there is still much to learn about them. However, of the techniques used in the industry for enhancing drug dissolution of poorly soluble drugs solid dispersions certainly appear to be the most versatile of formulation approaches and applicable for the majority of compounds and their dosing requirements.
- Amidon, G.L., et al. A theoretical basis for a biopharmaceutics drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. (1995), 12: 413-420.
- Butler, J.M. and Dressman, J.B., The Developability Classification System: Application of biopharmaceutics concepts to formulation development. J. Pharm. Sci. (2010), 99: 4940-4954.
- Guzmán, H.R., et al. Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of celecoxib from solid oral formulations. J. Pharm. Sci. (2007), 96: 2686-2702.
- Wyttenbach, N. et al. Miniaturized screening of polymers for amorphous drug stabilization (SPADS): Rapid assessment of solid dispersion systems. Eur. J. Pharm. Biopharm. (2013), 84: 583-598.
- Zhao, Y., et al. Prediction of the Thermal Phase Diagram of Amorphous Solid Dispersions by Flory–Huggins Theory. J. Pharm. Sci. (2011), 100: 3196-3207.
Dr. Robert Harris has held the role of chief technical officer at Juniper Pharma Services since 2010, providing technical steer to the company’s formulation development and clinical trial manufacturing services. Dr. Harris, has over 30 years of pharmaceutical industrial experience.