Chris Landeg, of Pharmaterials, looks at ways of speeding up the drug development programme by using new methods of assessing and improving the solubility of materials for new drug formulation
In many cases, drug development timescales are becoming shorter and pharmaceutical developers are always under pressure to formulate their new chemical entities (nces) quickly and effectively. This drives the constant need for new technologies and techniques to speed up the development of nces into suitable formulations while limiting the risks to such time effective approaches.
Another common trend is that many nces are poorly soluble, i.e. they are limited in their bioavailability by poor aqueous solubility. Two significant factors behind the increasing number of poorly soluble nces are the use of dimethyl sulphoxide (DMSO) in initial screening, allowing nces to progress that wouldn"t have been considered previously; and the general increase in the complexity and molecular weight of the nces, which increases the "organic" nature of the drug, often lowering the solubility in polar media such as water. This trend drives the need for new techniques to improve (kinetic) solubility of the nces.
This article discusses two new approaches to these current issues in formulation development that are used at Pharmaterials as part of the overall strategy of improved nce development. These are rapid screening of nce/excipient compatibility and use of stabilised amorphous formulation to improve kinetic solubility.
There is always an urgent need to decide which excipients can be used in formulation development of an nce, preferably before any work is carried out. Therefore, there is a requirement to assess nce or excipient compatibility.
The standard technique is to mix the nce and a range of excipients (often in the ratio of 1:9) and store the mixtures under accelerated stability conditions for at least a month (e.g. 40°C and 75% relative humidity). The chemical stability is then assessed using HPLC and/or NMR. However, this is a very slow process and the readout is achieved only after at least a month.
The development team is thus faced with a choice of whether to delay the formulation development for at least a month or "blindly" to start the development programme, with the risk of wasted effort if drug and excipient subsequently prove to be incompatible.
An alternative technique is needed to screen rapidly for nce/excipient compatibility to highlight those excipients that show some interaction and can therefore be discounted.
Previously, Differential Scanning Calorimetry (DSC) has been used to examine nce/excipient compatibility with limited accuracy of results. This approach involved mixing the nce and excipient together and running the DSC profile; i.e. heating from ~25°C to ~300°C and observing the heat flow associated with physical events (usually melting). The differences in thermographs between the profiles of the mixture and the components run separately indicated possible interaction and thus suggested incompatibility.
However, this technique is not ideal as thermal events could be masked and also the NCE may 'dissolve' in the excipient, which can lead to false results. A classical example of a false positive is that magnesium stearate melts and the drug dissolves in this hydrophobic molten mass, such that the drug melt is then lost. This would indicate an incompatibility, but in reality there is no chemical interaction. False negatives are also common due to limited particle-particle contact.
Another issue is that the constant steady change in temperature could make it difficult to distinguish genuine NCE/excipient interaction from the 'background' physical change events. Above all there is a fundamental issue to assuming that a chemical reaction that takes place at 200°C or above will also take place at 25°C.
An alternative approach has been developed at Pharmaterials using iso-thermal calorimetry. The principle is that any interaction between the NCE and the excipient should produce some heat change, either exothermic or endothermic, which should be observable by calorimetry. The process uses multi-channel DSC, but is run iso-thermally (i.e. at fixed temperatures with fast transition between the temperatures). The multi-channel configuration allows separate controls of the nce and excipient to be run concurrently and therefore subtract any background heat changes due to the materials (e.g. physical changes, such as water redistribution).
Any remaining heat changes in the mixed samples are then attributable to an interaction. The samples (pure components and mixtures) are held at several temperatures (i.e. isothermally at 40, 50, 60, 70°C) and any extra heat changes in the mixed samples are observed. Generally, interactions observed at lower temperatures are seen more intensely at elevated temperatures, providing further evidence of a genuine chemical interaction (rather than a physical form change). This gives an accurate readout of incompatible excipients in hours. These excipients can then be excluded from development work.
This is a significant advance over previous approaches when isothermal microcalorimetry has been used without the ability to change temperature rapidly. It is the observation of the reactions at different temperatures that allows the accurate assessment of interactions to be obtained.
For full confirmation, excipients that show no interaction can then be submitted to standard stability testing to confirm compatibility. However, the need for extensive stability trials is lessened and the formulation development can proceed with reduced risks and in a faster timescale.
Many nces show limited solubility in aqueous systems, which can limit the bio-availability (i.e. BSC class II, poorly soluble drug). There are various options to improve solubility, including salt formation, control of polymorph, control of particle size (e.g. micronisation, formation of nanoparticles), use of excipients such as lipids, cyclodextrins etc.) and the use of the amorphous state.
The amorphous state has limited short-term order to the solid material, i.e. no recognisable long-range crystalline structure. As high lattice energy of crystals is a major factor in decreased solubility, amorphous materials generally have faster (and higher) kinetic solubility. However, the disadvantage of using the amorphous state is that such materials can be unstable with respect to recrystallisation and are often more unstable and hygroscopic (i.e. they absorb water which encourages recrystallisation, hydrate formation or decomposition).
To use the improved kinetic solubility, it is necessary to stabilise the amorphous material. This can be achieved by dispersing the amorphous nce within an excipient, often one of the following: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or microcrystalline cellulose (MCC).
Pharmaterials has extensive experience in working with these materials. Some examples are shown in Figure 1. The graph shows concentration in solution versus time for the slurrying of the same quantity of nce made up as different formulations. The crystalline nce material (green trace) has low kinetic solubility. The other traces show the same nce, but formulated as amorphous dispersions in various excipients. The kinetic solubility is significantly enhanced.
Making the amorphous material in the presence of the excipient produces a stable formulation that has vastly improved solubility in dissolution testing (over 2-3 hrs). This improvement was supported by improved bioavailability of the stabilised amorphous formulations of the drug in subsequent pharmacokinetics testing (figure 1).
There are some practical difficulties in using amorphous materials. Initial research is carried out on a small scale, using techniques that are convenient for >1g material. The two main techniques used are solvent evaporation and ball milling. Both techniques will generate nce/excipient mixtures in ratio range of 1:2 to 1:10 nce:excipient on 100mg to 1g scale.
These materials have also been developed on a larger scale. Currently, ball milling is rarely used to make amorphous materials on an industrial scale in the pharma industry (although it is used in other industries). Solvent evaporation can be scaled up to ~200g-1kg quantities, but is often difficult to scale up further. So solvent evaporation can be used to initial scale-up, e.g. Phase 1 clinical trials, but is problematic for larger quantities. So most amorphous materials are developed for manufacture by spray drying, which is fully scalable in the pharma sector.
Two new techniques have been outlined to help the fast and effective development of solid dosage forms in the modern environment of needing rapid development of often poorly soluble drugs. These techniques form part of the range of technologies that are used at Pharmaterials to develop the efficient formulation of an nce.