Extrusion Processing of Pharmaceuticals
5.3 Polymer Selection for the HME Process
130 Handbook of Polymers for Pharmaceutical Technologies
PEGs and PEOs are semicrystalline, therefore having a tendency to form eutectic or monotectic mixtures with crystalline drugs. Poloxamers (Lutrol®) are also known to be excellent solubilizers, as well as plasticizers when used in mixtures with other polymers.
Polymethacrylate copolymers lack the solubilizing capacity of other polymers, but are excellent matrix formers, used for the sustained release of drugs, or for enteric release, depending on polymer chemistry. The ammonio-methacrylate copolymers (Eudragit®
RS/RL) are insoluble but permeable by water, a property that makes them suitable for the production of sustained release pellets. Poly(methacrylic acid-co-methyl methacry-late) 1:2 (Eudragit® S) and Poly(methacylic acid-co-ethyl acrymethacry-late) 1:1 (Eudragit® L), on the other hand, are soluble at pH values above 6 and 7 respectively, which makes them suitable for enteric release pellets.
Finally, the cellulose derivatives are mostly used as matrix formers for sustained release pellets due to their hydration and gel formation ability, with formation of a diffusion layer around the drug particles and delays its release into the dissolution medium. Certain cellulose esters, such as hydroxypropyl methylcellulose acetate suc-cinate (Aqoat-AS®) or cellulose acetate phthalate, are used for the production of enteric release pellets, because they are soluble in the mildly basic intestinal fluid.
From the above it becomes clear that there is a variety of chemically diverse poly-mers that fulfill the basic requirements, aimed at different applications. However, when it comes to HME processing, there are several considerations to be taken into account, beyond the polymers’ chemistry, and these include the polymers’ physical properties, thermodynamic considerations regarding drug-polymer miscibility and solubility, crystallinity of drug and polymer, polymer molecular weight, which greatly affects melt viscosity, and finally, the presence of plasticizers. These factors will be thoroughly dis-cussed in the following section.
Polymers as Formulation Excipients for Hot-Melt 131 A further complication to the definition of drug-polymer solubility arises from the fact that the dissolved (i.e., molecularly dispersed) drug exists in a metastable state relative to the crystalline drug, and therefore tends to reach thermodynamic equilibrium with the crystalline phase. This initial drug content is referred to as drug-polymer miscibil-ity and is of high relevance in pharmaceutics, since it can be kinetically stabilized for a sufficient amount of time to ensure acceptable shelf-life of the final product. The drug content at equilibrium with its crystalline phase is referred to as the solubility of drug in the polymer.
The above definitions are clarified in Figure 5.4 [28], where the optimal operat-ing conditions for the HME process for a particular polymer can be easily identified.
The binary system’s glass transition line poses the boundary between glass and liquid.
Usually the HME process is not feasible below the glass transition point of the system due to the excessively high viscosity, and therefore the glass region is of relevance only for the storage of the obtained solid dispersion and not for the operating conditions of HME. The crystalline drug solubility curve defines the boundary of the thermody-namically stable zone, where the system will not undergo phase separation under any circumstances. Zones I and II correspond to the glass and liquid, respectively, with zone II containing the optimal operating conditions for successful HME processing.
The upper boundary of the metastable zone is defined by the amorphous drug-poly-mer miscibility (spinodal) curve. The thermodynamic driving force for crystallization of the drug and phase separation is usually balanced by the kinetic hindrance, and the supersaturated melt is stabilized. If the dose requirements allow, the drug’s concentra-tion should be kept within region II, however, very often formulators face situaconcentra-tions where high-dose APIs have to be added in concentrations well within the metastable zone (zone IV). Depending on storage conditions, such a solid dispersion may be sta-bilized for years. Above the miscibility (spinodal) curve, phase separation is inevitable, as the thermodynamic driving force is very strong, and any solid dispersion produced by operating within zone VI will be of the solid suspension type.
Figure 5.4 Composition vs temperature diagram illustrating the concepts of drug solubility, and drug-polymer miscibility in relation to the binary system’s glass transition temperature. Reprinted with permission from [28], Copyright 2010 Wiley.
132 Handbook of Polymers for Pharmaceutical Technologies
Drug-polymer miscibility can be estimated within the framework of Flory-Huggins (F-H) polymer solution theory. The free energy of mixing, ΔGmix, is decomposed into two components: an entropic component, ΔSmix, that favors mixing, and an enthalpic component, ΔHmix, that may or may not favor mixing, depending on the type of drug-polymer interactions:
∆Gmix = ∆Hmix − ∆T Smix (5.1)
When the ΔGmix is negative, mixing will occur. According to the Flory-Huggins theory, the Gibbs free energy of mixing is expressed as a function of an F-H interaction param-eter, χ [29]:
∆ = + +
Gmix l
drug drug drug
poly
poly poly drug poly
RT Nf n N ln
f f
f cf f
(5.2)
where φ is the volume fraction, N is the molecular volume, R is the gas constant, T the temperature, and χ is the F-H interaction parameter. More specifically, Rubinstein and Colby define χ as “a dimensionless measure of the differences in the strength of pair-wise interaction energies between species in a mixture (compared with the same species in their pure component states)” [30]. Its value is used as an indicator of drug-polymer miscibility, with negative values (χ ≤ 0) indicating strong attractive interac-tion between drug and polymer, and therefore complete miscibility, low positive values (χ > 0) indicating weak repulsive interaction and partial miscibility, and large positive values (χ >> 0) indicating immiscibility.
The value of the F-H interaction parameter, χ, can be estimated on the basis of melt-ing point depression data collected by a suitable thermal analysis method, such as DSC:
1 1 1 1
0
2
T T
R H ln
m − m = − drug m poly poly
∆ + −
+
f f cf (5.3)
where Tm and Tm0 are the melting points of the drug crystals in mixture with the poly-mer, and in the pure state, respectively, R is the gas constant and ΔH is the drug’s heat of fusion.
Although the F-H interaction parameter, χ, expresses mainly the enthalpic contribu-tions to miscibility, it is not completely free of entropic components, and varies with temperature, T, and composition, φ [31]:
c= + +A B f+ f
T C1 C2 2 (5.4)
where A is an entropic, independent term, B is an enthalpic, temperature-dependent term, and C1, C2 are fitting constants. A simplified form of this equation has been found to provide satisfactory results when variation of χ with composition is negligible compared to that with temperature [30]:
c = +A B
T (5.5)
Polymers as Formulation Excipients for Hot-Melt 133 Another commonly used method of estimation of the χ parameter is the solubility parameter approach:
c=VRTsite
(
ddrug −dpoly)
2 (5.6)where Vsite is the volume of the lattice site, and d is the solubility parameter of the drug and polymer. Hildebrand solubility parameters are related to the cohesive energy density (CED) through the following equation:
d = CED = E
V
∆ vap (5.7)
where ΔEvap is the energy of vaporization, and V is the molar volume. Alternatively, the Hansen solubility parameters can be used, which include a dispersion, dd, a polar, dp, and a hydrogen bonding component, dh, as follows:
d2 =dd2+ +dp2 dh2 (5.8)
which in turn can be calculated using the group contribution method:
dd Fd dp p dh h
V
F V
F
=
∑
=∑
=∑
V (5.9)where Fd, Fp, and Fh are the group contributions at 25°C for the structural groups of organic molecules [27,32,33].
The upper drug-polymer miscibility boundary (spinodal curve, Figure 5.4) can be estimated by setting the second derivative of the free energy of mixing equal to zero:
1 1 2 0
f f c
drug +m poly − = (5.10)
where m is the ratio of the volume of a polymer chain to the molecular volume of the drug.
It has been found that for the majority of drugs, which have a molecular weight in the range of 200–600, and most common polymers with a molecular weight between 10,000 and 1,500,000, the ΔSmix is relatively constant [34], while the enthalpic param-eter, which depends largely on the polymer’s chemical structure, is more important in defining miscibility. Therefore, in order to improve the miscibility of a particular drug with a polymer, it is a much more efficient approach to select a chemically different polymer instead of switching to a homologous polymer of a lower molecular weight.
So far, the discussion has been focused on the amorphous solid solution type of dis-persions. However, not all polymers used in HME are amorphous, or capable of forming amorphous solid dispersions. In fact, some of the most common hydrophilic polymers, the poly(ethylene) glycols (PEG), are semicrystalline, and the crystalline region faces serve as templates promoting the crystallization of the dispersed or dissolved drug, thus
134 Handbook of Polymers for Pharmaceutical Technologies
forming mostly eutectic or monotectic systems [35]. The drug-PEG systems are consid-ered to be completely miscible in the liquid state but immiscible in the solid state. The aforementioned methods to predict drug-polymer miscibility are not applicable in the case of eutectic systems. However, considering that eutectics exhibit certain advantages, such as increased physical and chemical stability due to the absence of amorphous content, PEG and related polymers find wide applicability as solid dispersion carriers, a method to pre-dict the eutectic composition has been developed [35]. Starting from the van’t Hoff melting point depression equation, and utilizing the rates at which the eutectic point is approached (slopes of the liquidus line in the phase diagram) and the difference in the melting points of drug and polymer, a dimensionless index, Ic, was introduced, which can be used to predict the eutectic composition of these binary systems:
I T T
R T H
c
fd fp
fd fd
= −
( )
2/∆ (5.11)where Tfd and Tfp are the melting temperatures of drug and polymer, respectively, R is the gas constant, and ΔHfd is the heat of fusion of the drug. Basic requirements for the appli-cability of this equation are that the polymer is the major component (weight fraction of polymer, wp, >0.5) and its melting point is lower than that of the drug (Tfp ≤ Tfd). The proposed relationship between Ic and eutectic composition is illustrated in Figure 5.5.
Based on the difference between the melting points of the 50/50 drug/polymer com-position, T0.5, and the pure polymer, Tfp, the authors distinguish the following four cases, listed in Table 5.2 [35]:
Although this index has been developed to describe drug-PEG eutectic systems, it is expected to apply with reasonable accuracy in a variety of similar drug-semicrystalline polymer systems.
Solid phase
iv iii ii i Ic=0 Ic=1 Ic=2 Ic<3 Tp
wp= 0.5 wp= 1
Td Interactiondrug-polymer= 0
Interactiondrug-polymer>Interactiondrug-drug>Interactionpolymer-polymer>0 Liquid phase
Figure 5.5 The nature of PEG-drug phase diagrams and the proposed relationship between Ic and the eutectic point. Reprinted with kind permission from [35], Copyright 2002 Springer Science and Business Media.
Polymers as Formulation Excipients for Hot-Melt 135