Extrusion Processing of Pharmaceuticals
5.4 Processing of HME Formulations
5.4.1 Physical Properties of Feeding Material – Flowability, Packing and Friction
Polymers as Formulation Excipients for Hot-Melt 135
136 Handbook of Polymers for Pharmaceutical Technologies
stages of extrusion and different locations along the barrel. This is an advantage when shear- or temperature-sensitive materials are processed, because exposure time to high shearing forces and temperatures can be shortened [2].
Another important property of the feed material is the packing ability, expressed by Carr’s compressibility index, which is defined as the percent difference between the packing density of a densely packed powder following application of low com-pression, tapping or vibration, and a loosely packed powder, also known as bulk den-sity (equal to the weight of particulate feed poured into a cylinder divided by the occupied volume), divided by the packed density [41]. Index values < 20% ensure dense and uniform packing and filling of the feed material into the screw channels, and consistent supply and throughput of melt extrudate. Compressibility and volume reduction become important as the material is transported from the feeding zone to the heating/mixing zone of the screw. In the feeding zone, the root diameter of the screw is smaller and the channel depth greater, whereas in the mixing/heating zone the root diameter is larger and the channel depth smaller, resulting in compressive shearing.
Although free flow is required in the feed hopper, frictional forces play an impor-tant role as the material enters the feed zone. As soon as the material enters the feed throat, it is confined between the screw channels and the barrel wall, and ideally a plug should be formed [42]. For the efficient transport (pumping) of the formulation down the screw into the heating/mixing zone it is important that there is friction between the plug and the surface of the barrel, but minimal friction with the screw surface, allowing slipping. The friction may arise, for example, due to formation of a coherent plug and also due to adhesion between the heated plug entering the feed throat and the barrel wall. Consideration of the melting temperature or the glass tran-sition temperature range of the polymer is crucial in adjusting the temperature of the feeding zone so that there is adherence to the barrel wall but no sticking to the screw surface, which may result in the formation of a thick layer of molten polymer cover-ing the root of the screw and preventcover-ing entrance of further material [39]. Adherence of the feed material with the barrel wall can be increased using feed throats having longitudinal or spiral grooves on the inside walls, which is attributed to the capture of feed particles into the grooves, thus increasing the friction of the feed material with the wall [42].
5.4.1.1 Crystallinity 5.4.1.1.1 Polymer
Semicrystalline polymers, such as polyethylene (polyethylene glycol, polyethylene oxides, polyethylene-co-vinyl acetate, polyvinylacetate–co-methacrylic acid), polypro-pylene (Poloxamers) and polyamide (nylon), as well as carnauba wax, glyceryl palmi-tostearate and isomalts, have distinct melting points appearing as endothermic peaks in the DSC diagrams. On the other hand, amorphous copolymers involving two or more monomers like methacrylic, methacrylate, ethacrylate, vinyl pyrrolidone, vinyl alcool, vinyl acetate, and caprolactam, do not melt but undergo a transition into the rubbery state above their glass transition temperature, appearing in the DSC as a shift of the baseline in the endothermic direction. As the temperature increases above the
Polymers as Formulation Excipients for Hot-Melt 137 Tg, the polymer begins to flow and acquires the final rubbery state, allowing processing with the aid of shearing and heating, at a temperature several degrees higher than the Tg. Melting requires higher energy input for crystalline than for amorphous polymers, because in the former case, breaking of the intra- and inter-chain bonds holding the ordered polymer chains together is involved, whereas in the latter case (glass to rub-bery state transition) energy is required only for the disentanglement of polymer chains in the glassy state. There is no distinct difference between crystalline and amorphous polymers in the molten state, with the molecular weight playing a more important role at this state.
When cooling crystalline polymers, temperature has to be below the melting point in order to freeze the final extrudate dimensions. In rapidly crystallizing polymers, like those based on polyethylene or polypropylene, cooling rates and temperatures are critical for the development of crystal size [43]. Rapid quenching of the molten extrudate results in smaller crystals and lower degree of crystallinity, whereas slow cooling results in larger crystals of higher crystallinity. When cooling amorphous polymers, temperature needs to be below the Tg in order to freeze the final extrudate dimensions. Depending on the cooling rate and extrudate thickness, unfrozen, rub-bery material at temperature above the Tg may remain in the center, although the external part has been “vitrified.” Later, slow cooling of this central part may result in shrinkage and formation of voids which are visible in the transparent extrudate and which may affect drug distribution and mechanical properties of the extruded product.
Furthermore, there are differences between the shrinking behavior and mechani-cal properties of melts produced from amorphous and crystalline polymers, as they are cooled upon exiting the extruder die, which can be explained due to the different arrangement of polymer chains in the melt. After cooling, the chains in the amorphous polymer melt pack randomly, taking up more space, whereas in the crystalline melt they pack closer in ordered arrangement, resulting in greater shrinkage which contin-ues until equilibrium. As a result of this, the melts of amorphous polymers are expected to be softer and more deformable. The effect of shrinkage on the final thickness and, more importantly, on the length of extrudate may be quite substantial. Finally, the appearance of melts coming from amorphous and crystalline polymers is different, the former having a transparent or slightly hazy appearance due to the presence of impuri-ties of the melts and the latter having opaque appearance due to scattering of the light by the crystalline regions of the polymer.
5.4.1.1.2 Drug
Changes in drug crystallinity during HME are mainly related to the extruder opera-tion, and in particular to the extrusion temperature, which can be adjusted easily on any type of extruder, the residence time, which depends on the length of the screw and is shorter in twin-screw extruders due to the faster feeding, the exerted compressive pressures, which are higher in the single-screw extruder, and, finally, on the shearing rate, which is higher in counter-rotating twin-screw extruders [43,44,45]. For example, Keen et al. [46] studied the effect of process conditions on crystallinity of grizeoful-vin with copovidone (Kollidon® VA 64) comparing a twin-screw extruder operating in co-rotation or counter-rotation. The amorphous content was found to depend on the
138 Handbook of Polymers for Pharmaceutical Technologies
screw speed, extrusion temperature and mode of extruder operation, i.e., co-rotating or counter-rotating.
There are numerous reports in the literature about the effect of polymer type on the crystallinity of the extruded drug. Wegiel et al. [47] examined different polymers for their ability to inhibit crystallization of polyphenolic drugs by application of mid-in-frared spectroscopy. The crystallization inhibiting performance followed the order Eudragit 1000 > polyvinylpyrrolidone > hydroxypropymethylcellulose acetate succi-nate > hydroxypropymethylcellulose > polyacrylic acid. Bounartzi et al. [48] compared combinations of Eudragit® RSPO with two plasticizers in formulations with 15% w/w of the crystalline drug venlafaxine HCl, and found that combination of the polymer with citric acid gave amorphous drug dispersion due to hydrogen bonding between the drug, the citric acid and the polymer, whereas combination with Lutrol® gave crys-talline dispersion. Bruce et al. [49] found that cryscrys-talline drug guaifenesin formed amorphous dispersions with Eudragit® L100-55/triethyl citrate up to 25% w/w drug content, and that crystallization of excess drug occurred on the extruded tablet surface and could be suppressed by addition of hydrophilic PVP, PEG, PEO, poloxamer and polycarbophil. Djuris et al. [7] extruded carbamazepine with Soluplus® without the aid of plasticizer and found that for drug content up to 5% w/w a molecular dispersion is formed.
5.4.1.2 Molecular Weight and Viscosity
Besides crystallinity, molecular size affects the processing, the nature and the mechani-cal properties of the melt-extruded solid dispersion. Comparing two polymers of different molecular weights, the polymer with the higher molecular weight requires more energy for extrusion, due to higher melting temperature and melt viscosity, giv-ing extruded product with greater mechanical strength, stiffness and ductility, which are desirable characteristics for further processing (cutting, milling, etc.). Conversely, lower molecular weight polymers require less energy for extrusion due to their lower viscosity, giving product of lower strength and easy to flow, which is desirable for injec-tion moulding applicainjec-tions.
The dependence of the melt viscosity, η, of linear polymers of narrow molecular weight distribution on molecular weight (MW) is expressed by a simple power law equation [50]:
[h = kMW3 5. ] (5.12)
where k is a constant. From this it can be estimated that a twofold increase of MW results in tenfold increase in viscosity. However, the processing conditions, i.e., tem-perature and shear rate also exert a great influence on viscosity. Heating the polymers to temperatures about 40°C higher than the melting point or Tg, generally causes 10 to 100 times reduction of viscosity [51].
Shear rate (τ) is a function of rotation speed, S, of the extruder screw, on the radius of the extruder barrel, Rb, and of the radius of exit die orifice, Rd, according to the equa-tion [42,43]:
t =[(4 R S⋅ b2⋅ )/(p⋅Rd3)] (5.13)
Polymers as Formulation Excipients for Hot-Melt 139 For a small-scale laboratory type extruder L/D = 24/1 with barrel and die orifice radius 0.3 cm and 0.075 cm, respectively, the equation becomes τ=272·S from which it is inferred that τ can vary from τ=136 sec-1 for a slow operation speed of 30 rpm, to τ=408 sec-1 for a high screw speed of 90 rpm, with a profound effect on viscos-ity within the recommended processing temperatures [25]. Most polymers in the molten state exhibit pseudo-plastic behaviour, that is, viscosity decreases at higher shear rates. The dependence of viscosity on shear rate can be expressed by a power equation [52]:
h= ⋅K t(n 1−) (5.14)
where K depends on the polymer, and the exponent, n, varies between 0.25 and 0.9 for different polymer melts. As n approaches unity, the melt viscosity becomes less shear sensitive and for the special case of a Newtonian fluid, n=1 and K=η, with viscosity depending solely on the extrusion temperature. Conversely, polymer melts with low n values are more shear sensitive and shear rate and temperature settings should be optimized.
5.4.1.2.1 Co-Extrusion
The combined effects of temperature and shearing on melt viscosity are particu-larly important when more than one shear- and temperature-sensitive polymers are included in the formulation, as is the case in the process of co-extrusion. For this purpose, an Arrhenius equation of viscosity-temperature dependence can be applied in order to find a suitable temperature range, so that in combination with appropri-ate screw rotation speed and design (helix angle and channel depth in heating and metering zones), similar viscosities for both polymers are achieved that allow suc-cessful processing and co-extrusion. If the above is not possible, then selection of an appropriate plasticizer may solve the problem [26]. Co-extrusion of drug melts has been successfully applied by Quintavalle et al. [53], who combined the hydrophilic polyethylene glycol with the lipophilic microcrystalline wax to prepare a sustained release formulation of theophylline using a modified ram extruder. Dierickx et al.
[54] co-extruded poycaprolacone (core) of extrudate with polyethylene oxide (coat) to develop a multilayer dosage form of metoprolol tartrate and hydrochlorothiazide;
furthermore, they co-extruded hydrophobic ethylcellulose (core) with hydrophilic Soluplus® (coat) to develop a multilayered dosage form [55]. Further examples have been reviewed by Vynckier et al. [56].
5.4.1.2.2 Viscosity Range in Small-Scale Extruders
Polymers with low viscosity melts require a shallow channel of low depth in the metering section to generate sufficient pressure for efficient pumping to the exit die. Helix configuration may also be a consideration. In a small-scale laboratory extruder with L/D = 24/1 and screw diameter 0.6 cm (output between 0.2 to 2 g), the screw, in most cases, rotates at a speed between 30 and 90 rpm, corresponding to shear rate of 1368 sec-1 to 408 sec-1 (see above),and experiences pressures from 500 psi up to 2000 psi.
Therefore, since viscosity = shear stress/shear rate, providing feeding is not a problem, and processability of the polymers is achieved when the melt viscosity is in the range
140 Handbook of Polymers for Pharmaceutical Technologies
10–100 Pa·sec. This is feasible for certain polymers like polyethylene oxides (PEO), polyethylene glycols, waxes and polyvinyl caprolactam-polivinyl acetate-polyethylene glycol (Soluplus®) for both single and twin types of extruders but not for polymers with high Tg or melt viscosity like acrylic, methacrylic and methacrylate copolymers and also for polyvinylpyrrolidone grades at the extrusion temperatures normally employed for pharmaceuticals between 100–180°C, for which the use of plasticizers described in the following section is imperative for smooth extrusion.
5.4.1.2.3 Molecular Weight Distribution
At this point it should be taken into consideration that unlike small homopolymers, large copolymers are composed of chains with different lengths and compositions (di-block and tri-(di-block copolymers), leading to a wide molecular weight distribution with a mean molecular weight instead of a single value. Polymers with narrow MW range fol-lowing normal distribution can be processed within a wide temperature range, whereas polymers with broad or bimodal or skewed distributions can only be processed within a short temperature range. This is exemplified in Figure 5.6a–b.
Figure 5.6 Examples of different number MW distributions: (a) normal distributions of different width, (b) skewed and bimodal distributions.
Polymers as Formulation Excipients for Hot-Melt 141 If the MW distribution curve is tailing towards high molecular weight chains, i.e., skewing to the right (Figure 5.6b), the processing temperature for the low MW part of the polymer may not be adequate to melt the high MW, leading to the presence of unmelted polymer in the extrudate. Conversely, if the MW distribution curve is tailing towards low molecular weights, i.e., skewing to the left (Figure 5.6b), the processing temperature required may be too high for the low MW part, causing early melting of the low MW chains in the feed zone and feeding problems due to the transmitted heat from the heating/mixing zone. Most importantly, the heat may cause degradation of the low MW chains to even shorter lengths, resulting in different physical and mechanical polymer properties [57].
In addition to molecular weight considerations, the degree of branching also affects pro-cessing. Branched polymers are stiffer, and have higher viscosity and higher mechanical strength, which are proportional to the degree of branching [52].