Selection of Suitable Drug and Excipient Candidates to Prepare Glass Solutions by Melt Extrusion for Immediate Release Oral Formulations

Poorly water-soluble compounds with dissolution rate-limited low oral bioavailability present one of the major challenges in pharmaceutical development. There are many ways to increase the aqueous solubility of such compounds, including micronization, salt formation and formulation of the drug as a solid dispersion. For many compounds, however, decreasing the particle size may not lead to a significant or adequate increase in bioavailability. Salt formation may also be problematic, particularly with neutral compounds and weak acids. Solid dispersions, in which the drug may be present in the amorphous state, offer an attractive means of increasing the solubility and, therefore, potentially increasing the oral bioavailability of these 'problem' compounds (Figure 1).

The application of solid dispersions for increasing drug bioavailability is by no means a new field of pharmaceutical research. In their early paper on the use of solid dispersions, Chiou and Riegelman1 observed that: "It is believed that this relatively new field of pharmaceutical techniques and principles will play an important role in increasing dissolution, absorption and therapeutic efficacy of drugs in future dosage forms."

Since then, a great deal of research has been done on solid dispersions but only a few have been marketed; for example, griseofulvin in polyethylene glycol (Grispeg, Sandoz) and nabilone in polyvinylpyrrolidone (Cesamet, Lilly). The difficulties associated with these systems limiting the production of usable dosage forms have been well documented.2-5 This paper introduces the application of melt extrusion for preparing solid dispersions and discusses how best to select drugs and excipients suitable for this process.

Figure 1: Drug bioavailability in dogs (crystalline versus amorphous).

Solid dispersion

A solid dispersion is a homogeneous mixture of one or more active ingredients in a pharmacologically inert matrix (carrier) in the solid state. Table I shows the various classes of solid dispersion that can be produced and the type and number of solid phases present.

Determination of the solid dispersion type and number of phases present is crucial to understanding the product. In this review, the discussion will be restricted to glass solutions, which are potentially the most advantageous for increasing oral bioavailability.

There are three main reasons why formulation of a drug as a glass solution can lead to an increase in the solubility of the active component:

• unlike the crystalline state there is no lattice energy to overcome in the amorphous state, which reduces the thermodynamic barrier to dissolution

• the particle size of the components is maximally reduced to the molecular level

• the intimate presence of a hydrophilic carrier leads to an increase in the wetting of the active, and possibly an increase in the solubility of the active in the diffusion layer surrounding the dissolving particle.

The preparation of solid dispersions, particularly on a scale suitable for production has been discussed in a number of recent reviews.5,6 There are three general approaches to preparing solid dispersions. The first of these is solvent evaporation (including spray- and freeze drying), and this has been the preferred technique for use with compounds that decompose upon melting. Consequently, the solvent method allows the routine use of amorphous polymers such as polyvinylpyrrolidone (PVP) and hydroxymethylcellulose, which either do not melt, or degrade before melting. There are some disadvantages to solvent-evaporation that limit its application. Finding a suitable co-solvent with negligible toxicity for a hydrophobic drug and hydrophilic excipient can be problematic; large quantities of solvent often have to be used, which increases both cost and environmental impact. Achieving adequate drying is also problematic, as any residual solvent can plasticize dispersions, altering their physicochemical properties,1,2 and may have toxicity issues.

Table I: Classification of solid dispersions (A 5 amorphous, C 5 crystalline).

A second approach to manufacture is by mechanical activation such as co-milling. This can lead to disruption of the crystalline lattice and may induce local melting and formation of amorphous material.7,8 Disadvantages to this approach are ensuring complete conversion to the amorphous state and developing a reproducible/robust methodology.5

The third approach to solid dispersion manufacture is co-melting.

The co-melt method has not been particularly successful in preparing glass solutions, as the majority of products formed have contained the drug in a crystalline state (Table II). The formation of amorphous dispersions is favoured by rapid cooling, which can entrap the solute (drug) molecules in the solvent (excipient) matrix by almost instantaneous solidification.8–10 Degradation of components upon heating and miscibility in the melt are the limiting factors in many systems.

Table II: Drugs prepared as solid dispersions by the melt method (A 5 amorphous dispersion, C 5 drug present in crystalline form).

Melt extrusion. Melt extrusion has been used in the polymer industry since the turn of the century and the technique is employed in the manufacture of 50% of all plastic goods.11 Extruders are available in different configurations and designs for various processing applications. For melt extrusion within the pharmaceutical industry, screw extruders are predominately used because they were designed to

• incorporate and homogenize additives without exceeding degradation temperatures

• generate high shear stress for dispersion of components/additives

• homogenize two or more materials with different melt viscosities

• provide a uniform shear stress and heat history

• allow precise control of the mixing process.12

The recent resurgence of interest in melt extrusion in the pharmaceutical industry results from its potential advantages in solid dispersion production. During melt extrusion, the drug is incorporated into a polymer by melting or plasticizing both the drug and excipient using either one or two screws inside a heated barrel. The molten material is then cooled, typically on a chilled stainless steel conveyor belt. This approach may lead to formation of a glass solution of drug and polymer. For example, Grünhagen13 commented that following the processing of several dozen drugs using melt extrusion, approximately one third were prepared as glass solutions.

Equation 1 and Figure 2: DSC/TGA of piroxicam, showing onset of degradation before melting. The upper trace shows TGA and degradation onset at 198 ÞC and the lower trace shows the DSC of the drug melting at 205 ÞC.

Melt extrusion is essentially a combination of melting and mechanical preparation methods, but has several advantages compared with both. Melt extrusion is cost-effective, continuous and reproducible - and allows for a high-throughput.11 Drug degradation is decreased compared with co-melt methods because of the increased input of mechanical energy and the use of a closed barrel that can be flushed with nitrogen to decrease oxidation reactions. Melt extrusion does not require solvents and is not, therefore, associated with the environmental, toxicological and financial implications of the use of large solvent volumes. Importantly, melt extrusion for the formation of glass solutions allows the use of thermoplastic polymers that do not melt. PVP is an example of a thermoplastic polymer, as its viscosity decreases with increasing temperature and the presence of plasticizers. Polymers such as PVP confer increased physical and chemical stability to amorphous systems.

The major disadvantage of the technology has been that even when a lab-scale extruder is used, a large quantity of drug material is required, which may not be available at an early drug development stage. This problem has been partially resolved with the development of small-scale, benchtop extruders such as that produced by ThermoHaake,14 which can process approximately 5-10 g of input material. However, even gram quantities of drug still remain problematic in early development, particularly as companies seek to incorporate potential formulation strategies in candidate selection. The remainder of this article addresses two key questions:

1. How should compounds that are suitable for melt extrusion be selected at an early stage of drug development using only milligram quantities of drug substance?

2. How should a suitable excipient matrix for melt extrusion with the compound be selected to ensure a glass solution can be manufactured?

Drug selection

For a drug to be suitable for melt extrusion, the glass solution produced must show an increase in dissolution rate compared with the crystalline drug and the product must be physically and chemically stable. Glass solutions are metastable and poor physical stability is the major factor limiting their use in drug delivery.5 For drug candidate selection to be successful, an indication of the likely physical stability of the product must be given.

Figure 3: Chemical stability of beaker melts and extrudates as measured by HPLC (drug/PVP melt, drug/PVP extrudate). Reproduced with permission from Drug. Dev. Ind. Pharm and Figure 4: X-ray powder diffractograms of amorphous (red) and crystalline indomethacin (black).

One method of predicting the physical stability of a glass solution is determination of the glass transition temperature (Tg).2,15,16 To increase the chances of forming a stable product, the Tg should be well above the storage temperature - with some authors recommending that the Tg should be approximately 50 °C above the storage temperature.15 At temperatures above the Tg, the amorphous material will change from a hard, brittle material into a less viscous rubbery state, which is more prone to recrystallization17 and also difficult to process.5 The Tg of a glass solution can be determined by differential scanning calorimetry (DSC) or predicted using the Gordon-Taylor equation (Equation 1).

The Tg of an amorphous drug can be determined experimentally using DSC or it can be estimated from the melting point based on the empirical relationship Tg5melting point30.7 (Kelvin). Depending on the quantity of drug available and the physical stability of the amorphous drug, the true density can either be measured or estimated. True density values for amorphous low molecular weight pharmaceuticals are typically in the range of 0.86-2.0 gcm-3.15

To begin the drug selection process for melt extrusion, it is necessary to examine the drug in combination with a suitable carrier. The hydrophilic polymer PVP has been used successfully to form glass solutions with a variety of poorly water-soluble drugs13 and is a suitable excipient for preliminary studies on drug selection. The major limitation to the use of PVP is that it begins to degrade at temperatures in excess of 150 °C.18 Previous studies, however, indicate that as long as temperatures do not exceed 190 °C for long periods, the thermal stability of PVP should be acceptable.18 For drug selection, this means that compounds with a melting point higher than 200 °C are not suitable for extrusion with PVP alone. Additionally, the majority of useful matrix excipients are prone to degradation above these temperatures and, therefore, additional plasticizing and/or solubilizing agents will be required, which may effect the stability and dissolution rate of the glass solution formed.

Figure 5: Glass transition temperature of indomethacin/PVP/VA (1:1) glass solutions determined by MTDSC (u) and predicted by the Gordon-Taylor equation (--).

Small-scale preparation of glass solutions/solid dispersions. DSC is an ideal means of preparing solid dispersions on a 5-10 mg scale. DSC is routinely available to most pharmaceutical companies, allows excellent control of temperature (heating/cooling rate) and provides information regarding the solid state properties of the material. In addition, the use of a nitrogen purge gas will allow compounds prone to oxidation at elevated temperatures to be investigated. Hot stage microscopy (HSM) has similar advantages of scale and will be discussed further as a preparative technique.

A second option is to perform small-scale stainless steel beaker co-melts, incorporating limited shear stress in the form of stirring. Cooling of the co-melt can be easily achieved by partially submerging the beaker into ice cold water or pouring the melt onto a cold stainless steel surface. For analysis of the material, it is normally necessary to lightly grind the material into a powder, which can then be sieved to select an appropriate size fraction. Care should be taken when applying any mechanical processing not to change the solid state of the product. As described earlier, it should also be noted that co-melting often does not lead to glass solution formation. The authors found that beaker melts often resulted in incomplete melting of the drug and the production of some residual crystallinity in the solid systems. However, it was also found that the majority of the beaker melt product was produced as a glass solution and therefore, given the dearth of alternative approaches, stainless steel beaker co-melts are a useful preparation technique.18 The use of beaker co-melts is somewhat less attractive now because of the availability of small-scale melt extruders. However, these devices are comparatively expensive and are likely to be time-consuming to use.

Figure 6: Drug selection protocol for melt extrusion (1 5 melting point