Processing Characteristics 751 Hydrophilic Matrices

Hydrophilic matrix tablets can be manufactured by DC, wet granulation, dry granulation (roller compaction or slugging), or hot melt granulation/extrusion, depending on the drug, the formulation, and available equipment. HPMC polymers generally have very good compressibility, producing tablets with high mechanical strength [56]. High molecular weight grades may exhibit less plastic flow, requiring higher compaction pressures for deformation [54].

Wet (aqueous) granulation of hydrophilic matrices requires a spray system for application of the liquid binder to avoid forming a lumpy mass [127]. However, a binder may not be necessary with HPMC-containing matrices as this polymer has excellent binder properties. Overgranulation or use of high binder concentrations can adversely affect compressibility. If water is the granulating fluid, its uptake by the granulate can be slow as it causes surface hydration of the HPMC, with swelling and barrier formation resisting penetration. Hence modest quantities of granulating fluid are advised. Hydroalcoholic solutions have better penetration, reducing surface hydration, with faster and better solvent uptake [128]. Higher amounts of such granulation fluid are usually required but the resulting granules can be uniform, nonlumpy, and less friable and can provide superior tablet compacts.

A novel foam granulation approach has recently been introduced [129]. Air is incorporated into a solution of conventional water-soluble polymeric binder such as a low viscosity grade HPMC to generate foam. This improves distribution throughout the granulate and reduces the volume of granulating solvent required.

Hot melt granulation or extrusion can be used to prepare ER systems, although manufacturability is strongly dependent on the formulation (drug, polymer, etc). Numerous successful examples have been reported, particularly using PEO and HPC compositions [102, 130-132].

Techniques such as DC or wet granulation do not generally affect release from compacts, provided these have sufficient mechanical strength and contain optimized levels of polymer(s) [133]. Melt granulation or melt extrusion variables, however, may affect performance. Roth and coworkers compared a hot melt-extruded vera-pamil HCl formulation based on hypromellose/HPC with a matrix formulation manufactured using conventional technology comprising wet granulation, blending, and compression, to assess abuse deterrence propensity and dose dumping in the presence of ethanol [130]. Figure 7.3 illustrates the differing alcohol resistances of the melt extruded formulation and the conventional wet granulated product in in vitro dissolution tests. It was hypothesized that melt extrusion can lead to greater chain entanglement and a stronger gel layer.

PEO-based injection molding has been used to manufacture abuse-deterrent units that did not exhibit dose dumping in the presence of alcohol. Furthermore, there was no food effect (fasting vs. fed state) and release was consistent as well as prolonged, compared to units prepared by DC or wet granulation [134-137].

The mechanical attributes of hydrophilic matrices may be affected by manufacturing method. Melt granulation or use of hydroalcoholic solutions generally provide superior compacts to those incorporating granules formed by aqueous granulation, or to DC units [128]. Such differences in compact strength may reflect compact porosity. However, mechanical strength may have little influence on drug release when tablets are made with sufficient strength (to withstand handling) and contain optimized levels of polymer. A precompression step may ensure consistent porosity and avoid entrapment of air during compression.

Compression speed can affect tablet tensile strength [50-52]. Inclusion of small amounts of hydrophilic polymer as intergranular excipient (the remainder being added as extragranular component) may result in more robust compacts [45].

Wet Granulation Theory
Fig. 7.3 Release profiles of Verapamil HCl hydrophilic matrix products prepared by (a) conventional technology of wet granulation, blending, and compression. (b) Melt extrusion in dissolution media with varying levels of ethanol (Reprinted with permission from [130])

7.5.2 Inert Matrix-Based Systems

Conventional manufacturing processes such as wet granulation [111] and DC [108-110] are appropriate for most inert-matrix systems. Melt extrusion also possesses advantages [108]. However, manufacturing variables and material attributes can affect release from inert matrices. Release can be influenced by porosity and tortuosity of the matrix. The type and level of pore former (water soluble or insoluble) can dramatically alter such porosity and tortuosity. Inclusion of water-insoluble excipients in inert matrices can reduce matrix wettability, reducing penetration of the dissolution medium and slowing drug release. Water-soluble excipients can enhance wetting or matrix porosity, providing faster drug release. Higher compaction forces during tableting generally leads to lower porosity and

Characteristics Oral Medication

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Fig. 7.4 Dissolution rate of ethylcellulose systems based on manufacturing process and ethylcel-lulose particle size (Reproduced with permission from [108])

0 50 100 150 200 250 0 50 100 150 200 250

Fig. 7.4 Dissolution rate of ethylcellulose systems based on manufacturing process and ethylcel-lulose particle size (Reproduced with permission from [108])

slower release. Particle size of insoluble matrix formers can also influence release rate, larger particles producing matrices with more open structures and faster release.

Crowley et al. showed that the physical properties of ethylcellulose-based matrices reflected the matrix polymer properties and manufacturing process [108]. Ethylcellulose-based systems incorporating coarse particle size polymer (30-80 mesh) had significantly greater pore size, porosity, and tortuosity than systems prepared using fine-particle material (80-325 mesh). The difference was significantly greater in tablets prepared using DC. Melt extrusion, in contrast reduced particle-related differences. Dissolution rate was lower in melt extruded systems having lower porosity and greater tortuosity (Fig. 7.4).

7.5.3 Choosing the Matrix

Matrix gel formers and insoluble matrix systems each have unique features that need to be considered when considering the dosage form design strategy. Available manufacturing technology is also important. Cost of goods, target release, and plasma profile and food effects need to be considered as well as drug-excipient compatibility. Gel forming and insoluble matrices are both economic (low cost) operations and generally employ conventional processes (apart from melt extrusion equipment). Formulations based on hydrophilic matrix polymers are generally more robust in terms of sensitivity to minor variations in raw materials or manufacturing processes. Inert matrix systems generally tend to be more sensitive to such variations. However, formulations based on insoluble matrices generally tend to be more robust with respect to dissolution hydrodynamics, but be more sensitive to GI motil-ity effects and "exhausted ghost" behaviors.

In some cases, the manufacturing process can increase polymer chain entanglement and gel strength, leading to improved hydrodynamic performance [130]. Novel techniques such as the multilayer Geomatrix® (SkyePharma) tablet may provide unique advantages for designing zero-order release profiles using conventional hydrogel-type matrices. Ultimately, careful regulation of gel strength and porosity by employing a combination of formulation additives and manufacturing techniques can facilitate the design of systems with the desired release characteristics.

It may be possible to evaluate or estimate performance a priori using mathematical models such as the sequential layer method [29]. Additionally, commercially available systems can be used to predict desired formulations based on molecular properties. The most notable of these systems is the HyperStart™ program [138], which utilizes properties of the compound, such as solubility, as starting points for formulation development.

Small-scale studies on compaction effects on matrix performance are also valuable. Making tablets at controlled pressure requires appropriate tablet instrumentation. Small (bench) scale apparatuses are now available for such a purpose, providing a wide range of compaction forces, minimal use of materials, and easy setup [139]. As these and other systems continue to be refined, their utility (and limitations) will become more evident.

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