Chapter 2

Application of Polymer Combinations in Extended Release Hydrophilic Matrices

Ali Nokhodchi*,1,2, Dasha Palmer3, Kofi Asare-Addo4, Marina Levina5 and Ali Rajabi-Siahboomi6

1School of Life Sciences, University of Sussex, Brighton, UK

2Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

3Lake Life Sciences, Lake Chemicals & Minerals Ltd., Worcestershire, UK

4School of Applied Sciences, Pharmacy Department, University of Huddersfield, West Yorkshire, UK

5GlaxoSmithKline GMS, Ware, Hertfordshire, UK

6Colorcon Inc., Global Headquarters, Harleysville, Pensylvannia, USA

*Corresponding author: A.Nokhodchi@sussex.ac.uk

Abstract

Extended release (ER) oral dosage forms provide a number of therapeutic benefits (i.e., improved efficacy, reduced frequency of administration and better patient compliance) and retain market share. Due to the costs involved in discovering, developing, testing their safety and getting approval for new polymeric materials, a new focus has been directed towards the investigation of the use of pharmaceutically approved polymer blends as matrix formers. Combining polymers of different chemistries or viscosities has been studied extensively as a means of achieving and optimizing extended drug release from hydrophilic matrices. The present chapter will discuss the potential use of binary blends of various polymers to achieve the desirable release profiles.

Keywords: Hydrophilic polymers, polymer blend, swelling, drug release, matrices, compatibility, synergistic effect, ionic polymers

2.1 Extended Release Matrices

Among various medicinal dosage forms, tablets account for approximately 80% of the drug delivery systems used today due to their ease of manufacture, convenience of dosing and stability compared with liquid and semi-solid approaches [1].

The ER formulations provide therapeutic benefits such as improved efficacy and reduced side effects with reduced frequency of administration and, therefore, better patient compliance, and retain market share for the manufacturer [2-5]. Among ER formulations, matrix systems remain the most popular approach from the economics of development and manufacture as well as from the process control and scale-up points of view [1,6-9]. The most prevalent are hydrophilic matrices, which most often provide a desirable drug release profile, are cost effective and have a broad regulatory acceptance [5,10-12].

The majority of commercially available matrix formulations are in the form of tablets, and although developing them may initially seem simple, the formulation scientist is required to consider a number of variables that influence drug release, as well as the manufacturing and processing of these tablets. The release rate from the matrices is dependent upon drug characteristics; particle size, solubility and dose, release controlling polymers; type, level and particle size, fillers; type and level, tablet properties; porosity, tortuosity (affected by compression force) and shape [13-35].

2.1.1 Polymers Used in ER Matrices

There are a number of different macromolecular polymers that can be used to modify drug release from ER matrices. These can be classified into water soluble and water insoluble polymers. The full list of FDA-registered oral ER formulations containing commonly used hydrophilic or water-insoluble polymers together with their approved maximum potency levels are reported elsewhere [36].

2.1.2 Water-Soluble (Hydrophilic) Polymers

Amongst the various water-soluble or water-swellable polymers with high molecular weight used in hydrophilic matrices, hypromellose (hydroxypropylmethylcellulose [HPMC]) is the most commonly used polymer [5,13,37-40]. Other polymers have been studied and used on their own or in combination with HPMC to successfully modulate drug release. Examples include polyethylene oxide (PEO), with a recent review looking at its application in controlled release tablet systems [41]. Typical water-soluble hydrophilic polymers used may be classified based on their chemistry as follows:

• The cellulose derivatives of hydrophilic polymers including hydroxypropylmethyl cellulose (HPMC, hypromellose), methyl cellulose (MC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC) and sodium carboxymethylcellulose (Na CMC) [5,23,37,38,43-50];
• Non-cellulose derivatives including polymethacrylates, gums/polysaccharides such as sodium alginate (Na Alg), xanthan gum (XG), carrageenan, chitosan, guar gum (GG) and pectin [5,12,42,51-56];
• Vinyl polymers such as poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP) [42,44,57-62];
• Poly(alkelenes) like poly(ethylene oxide) (PEO) [5,42,63-70].

2.1.3 Water-Insoluble Polymers

Commonly used polymers for the development of inert matrices are ethyl cellulose (EC) [43,71-78], methacrylate amino ester copolymers and poly(butylmethacrylate) [79-83].

2.1.4 Fatty Acids/Alcohols/Waxes

To manufacture hydrophobic ER matrices the following materials are used: fatty acids such as carnauba wax, paraffin wax and cetyl alcohol [5].

2.2 Polymer Combinations Used in ER matrices

Due to the high costs involved in development and safety assessment (tox studies) of new polymers, to obtain acceptability in the market place, scientists use a combination of pharmaceutically approved polymers. This approach is to enhance the performance of the ER matrices as compared to single polymers. These are acheived by obtaining a variety of physical and chemical synergies between the polymers to enhance their properties in the formulation [84-87].

Polymer blends can be employed in the design of more robust formulations with more predictable in vivo release, i.e., less prone to dose dumping, reduce burst release; more resistant to media agitation (resembling food effect); with enhanced solubility and/or stability of some APIs [88-91]. Development and manufacture of ER matrices of freely water-soluble active substances, particularly where a high dose is used, is often challenging. This is due to a potential 'burst' release during the initial stages of dissolution, thus making the once daily dose difficult. In such cases, for example, a combination of hydrophilic polymers, one of which may be ionic in nature, is used to design ER matrices with a more prolonged drug release profile as compared to formulations where single polymers are used [49,92-97].

2.2.1 Compatibility and Miscibility of Polymers

The functional properties of the blends depend upon the miscibility of the polymers at the molecular level, i.e., preference is given to the blends with mutual attraction of macromolecules in dilute aqueous solutions compared to immiscible ones [85,87]. Miscibility will only occur when a strong specific interaction is present within the dilute solution system, such as random dipole, induced dipole, dipole-dipole, ion-dipole, H-bonding, acid-base, and charge transfer interactions. For example, XG and Na CMC have been shown to be incompatible due to the presence of the enzyme cellulase in the former, causing breakdown of Na CMC structure, resulting in a decrease of viscosity [98]. Whereas the combinations of ionic polymers (i.e., Na CMC or carbomer) with non-ionic hypromellose were found to produce synergistic interactions leading to an unexpected viscosity increase [99].

The mechanism of this type of interaction would normally depend on factors such as crosslinking of H-bonds between hydroxyl groups, nature of the polymer, degree of substitution, polymer chain configuration and length [98]. Generally, the crosslinking between different species would be greater compared to interactions between similar molecules due to formation of stronger hydrogen bonding. For instance, the H-bonding between a carboxyl group of Na CMC and a hydroxyl group of HPMC would usually be greater than between two hydroxyl groups of HPMC. The H-bonding would also be more prominent in the longer side-chain polymers, where a larger number of groups is available for the interaction to occur.

Thermodynamic interaction parameters can be calculated using the Flory-Huggins theory of mixing. In a study by Fuller et al. [100], looking at the interactions in PEO and HPMC blends, a Flory-Huggins interaction parameter, x12 (which was defined to describe the enthalpy of mixing), was related to the interaction energy density (B), the gas constant (R), the observed equilibrium melting point of blended PEO (Tm) and to the molar volume of the repeating units of HPMC (V1u); where subscripts 1 and 2 refer to HPMC and PEO, respectively (Equation 2.1). The HPMC-PEO films made from N,N-dimethylacetamide (DMAc) and water yielded negative values for the interaction parameter, indicating a miscible blend [100].

(2.1)

Karavas et al. [101] analyzed drug release from miscible polymer blends (PVP/HPMC and PVP/chitosan) prepared using the solvent evaporation technique. DSC studies revealed that both blends were miscible in the entire composition range because only one glass transition temperature was detected in polymer mixtures. Miscibility was attributed to the strong hydrogen bonding interactions between the carbonyl group of PVP (which acted as a strong proton acceptor) with hydroxyl and amino-groups of HPMC and chitosan (which...