1. Drug Properties
Drug solubility and dose are the most important factors to
be considered in the design of ER matrices. In general, the extended-release
formulation of an extreme drug solubilities coupled with a high dose is
challenging. Drugs with very low solubility (e.g. <0.01 mg/ml) may dissolve
slowly and have slow diffusion through the gel layer of a hydrophilic matrix. Therefore,
the main mechanism of release would be through erosion of the surface of the hydrated
matrix. In these cases, the control over matrix erosion to achieve consistent extended
release throughout the GI tract is critical. For drugs with very high-water solubility,
the drug dissolves within the gel layer (even with a small amount of free
water) and diffuses out into the media. Therefore, it is important to control
the factors that affect drug diffusivity (e.g. pH, gel strength and
availability of free water) within the gel layer and parameters that ensure
integrity of the gel layer after the drug has been dissolved and released from
the gel layer. For poorly soluble drugs, the particle size of the drug has a
major influence on its release profile. A decrease in particle size of the drug
causes an increase in solubility and hence a faster drug release rate.
2. Polymer Considerations
Depending on dosage size and desired release rate, the
typical use level can vary from 20 to 50% (w/w). For drugs with high water
solubility, there is a threshold level of polymer for achieving controlled
release, and further increases in polymer level may not decrease the drug
release rate. However, for obtaining a robust formulation with consistent performance
and insensitivity to minor variations in raw materials or manufacturing processes,
a usage level of 30% (w/w) has been recommended. The particle size of the
polymer is also an important factor. The finer the particle size, the faster
the rate of hydration of the polymer and hence better the control of drug
release. Coarser polymer particles used in a direct compression formulation
have been reported to result in faster drug release than finer particles. The course
the particle size, the slower the hydration rate and gel layer formation.
3. Presence of Other Excipients
Fillers: Soluble fillers (e.g. lactose), insoluble
fillers (e.g. microcrystalline cellulose, dicalcium phosphate) and/or partially
soluble fillers (e.g. partially pregelatinized starch). Fillers are generally used
in hydrophilic matrices to enhance pharmaco-technical properties of tablets
(improve compressibility, flow and mechanical strength) or to modify the drug
release profile. The inclusion of fillers affects the dissolution performance
of a matrix by a "dilution effect" on the polymer. The magnitude of
the effect on the performance of matrices is dependent on the drug, the polymer
level and the level of excipient itself. The presence of water-soluble fillers
in high concentrations in the matrix leads to faster and greater water uptake
by the matrix, resulting in weaker gel strength, higher erosion of the gel
layer and therefore faster drug release. Insoluble but weakly swellable fillers,
such as microcrystalline cellulose, remain within the gel structure and
generally result in decreased release rate. The presence of partially
pregelatinized starch, such as Starch 1500®, in HPMC matrices has been reported
to decrease the drug release rate. For a highly soluble or sparingly soluble
drug, the rank order of release rate was as follows:
Lactose > Microcrystalline cellulose > Partially
pregelatinized starch
4. Release Modifiers and Stabilisers
Drugs with pH-dependent aqueous solubility (weak acids or
bases) are formulated in HPMC matrices, and they may exhibit pH-dependent drug
release. Formulating CR matrices of such drugs may lead to lower drug release
due to exposure of the dosage form to increasing pH media of the GI tract (from
pH 1.2 to 7). Formulating pH-independent CR matrices for such drugs would not
only ensure adequate release throughout the physiological pH range but also
lower intra- and inter-patient variability. Development of such pH-independent
matrices for weakly basic drugs has been shown with the incorporation of acidic
excipients (weak acids or salts of strong acids) that lower the
micro-environmental pH within the gel layer and thus maintain high local
solubility of the drug independent of the external release media.
5. Effect of Salts and Electrolytes
In general, as the concentration of ions in a polymer
solution increases, polymer hydration or solubility decreases. The amount of
water available to hydrate the polymer is reduced because more water molecules
are required to keep the ions in solution. Moreover, the types of ions in
solution affect the polymer hydration to varying degrees. The susceptibility of
cellulose ethers to ionic effects follows the lyotropic series of the ions (chloride
< tartrate < phosphates and potassium < sodium). Changes in the
hydration state of a polymer in solution are manifested primarily by changes in
solution viscosity and turbidity or cloud point. At low ionic strengths, the
polymer hydration is unaffected, but at higher ionic strengths may lead to a
loss of gel integrity of the matrix. The extent of this influence depends on
the polymer type and lyotropic series of the ions. The effect of electrolytes
or salts is important only in cases where high concentrations of salts or electrolytes
are present as tablet components or as constituents of dissolution media. In
vivo conditions, however, have fairly low ionic strength (ionic strength of gastrointestinal
fluids, 0.01-0.15), to affects the polymer hydration and has a significant impact
on the release rate.
6. Characteristics of Dosage Form
Variation in tablet shape and size may cause changes in
surface area available for drug release and hence influence drug release
profiles from HPMC matrices. A constant surface area to volume ratio (S/V) of
different-sized and shaped tablets for an HPMC formulation would lead to
similar drug release profiles. The size of the tablet may also dictate the
polymer level requirement. Smaller tablets have been reported to require higher
polymer content because of their higher surface area to volume ratio and thus
shorter diffusion pathways. One technology proposed for modifying the matrix
surface area to volume ratio was by physical restriction of the swelling of the
hydrophilic matrix by partially coating the matrix with insoluble polymers or
multi-layered tablets (Geomatrix® technology).
7. Presence of Coating
Application of film coatings to tablet formulations is a
common practice in the pharmaceutical industry. Tablets are coated for a
variety of reasons, such as improving the stability of the formulation, taste
masking, enhancing the aesthetic appearance, identification and branding,
improving the packaging process or modifying the drug release profile. Coating
of hydrophilic matrices with water-soluble polymers such as Opadry® or low-viscosity
HPMC generally does not alter drug release profiles. Coating with water-insoluble
polymers such as ethyl cellulose with or without permeability modifiers (e.g.,
low viscosity grades of HPMC or Opadry) may be used for modulating the drug
release profile from HPMC matrices.