CONTRACT SERVICES – Injection Molding in the Pharmaceutical Industry


INTRODUCTION

Many of the processes used to manufacture products within the pharmaceutical industry are unique to the particular product; however, there are also processes that have been borrowed and adapted from other manufacturing industries and successfully employed in the development of pharmaceutical products. One such example is injection molding (IM); a process developed in the late 19th century for the manufacture of simple plastic objects, such as combs, and later extended to all manner of parts made from thermoplastic and thermoset resins. Parts made by IM that are widely used in the pharmaceutical industry include caps, seals, closures, valves, syringes, inhalers, and the like. As with other plastic processing technologies that enable pharmaceutical solutions for otherwise difficult problems, IM is now gaining in popularity for manufacturing more complex device parts, and is even the platform of choice for preparing certain proprietary drug products.

THE MOLDER

The major components of an injection molder are shown in Figure 1 he IM process involves four essential steps:
1. Melting of material
2. Mass transfer of molten material from an injector into channels called “runners” in the mold and finally into the mold cavity
3. Hardening of the material in the mold to the shape of the cavity
4. Ejecting the part from the cavity to produce the final product

The earliest injection molders used a simple piston to force molten material into the mold. Modern molders use a combined heated barrel/screw/ram assembly in which the solid material is fed to the hopper of the heated barrel, where it is melted by a combination of the heat from the heater bands and the shear forces between the material, screw, and barrel. The molten material is conveyed by the screw toward the nozzle at the end of the barrel, and the screw then travels forward in the barrel as a ram to inject the material into the mold on each cycle. The addition of the screw also allows for some mixing so that multiple feedstocks can be added simultaneously to prepare for example colored parts, or to reuse scrap from previous runs. Two examples of pilot-scale injection molders from Nissei and Arburg are shown in Figure 2. AB Insturments, Thermo Haake and Alba are among makers of lab-scale injection molding units.

Molders can be hydraulic, electric, or pneumatic, with electric or pneumatic being preferred for pharmaceutical applications due to the potential issues of clean room contamination from hydraulic fluid aerosols. IM machines range in sizes from tabletop versions making micro-parts a few millimeters in size or smaller, to large-scale production machines requiring clamp pressures of the order of thousands of tons to hold the mold halves together during the molding process.

MATERIALS

Materials that are solid at room temperature must be heated above the meting temperature (Tm) before being pumped into the mold cavity. The temperature of the thermoplastic material needs to be raised sufficiently above Tm to reduce its melt viscosity and allow transfer from its reservoir to the mold cavity at manageable pressures. The higher the temperature above Tm, the lower the melt viscosity and hence the lower the pressure required to pump the material through the runners into the cavity. Of course, elevated temperatures accelerate thermal degradation (of polymers, additives, and drugs), so the lowest temperature that allows for reproducible part production should be used. Thermoplastic materials with glass transition temperatures (Tg) above room temperature form hard parts upon cooling, and suitable materials include resins, such as polystyrene, poly(methyl methacrylate), polypropylene, and polyethylene. Thermoplastic materials with Tg below room temperature (thermoplastic elastomers) form rubbery parts on cooling, and example materials suitable for IM are ethylene vinyl acetate copolymers (EVA, eg, VitalDoseTM), various polyurethanes (eg, ChronothaneTM, ElasthaneTM, Tecoflex®), polystyrene-polyisobutylene block terpolymers (eg, KratonTM), polyether-polyamide block copolymers (eg, Peebax®), and polyvinylbutyral (eg, Butvar®).

When the material is a liquid at room temperature, and cures in the mold by a chemical reaction to form the final part, the process is called reactive IM (RIM) and is exemplified by silicone elastomers in which low molecular weight reactive silicone liquids are cured in the mold at elevated temperatures by Platinum-catalyzed or Tin-catalyzed crosslinking reactions. Cycle times are typically longer for silicones than for thermoplastic products, as the part must cure before being ejected from the mold, and this is usually slower than simple cooling.

MOLDS

Molds are made of metal plates that have precision machined cavities in which the part cools or cures to take its final form after the material is injected into it. At the smallest tabletop injection molder scale, molds are mostly made from aluminum to save on costs and an example o-ring mold is shown in Figure 3. Production molds for medical and pharmaceutical applications are made of stainless steel of appropriate regulatory grade. Depending on the size and complexity, the cost of molds can range from a few thousand dollars and can go up to several hundreds of thousands.

The runners may be embedded within the plane of the cavity in the mold and filled with polymer from the injection nozzle on each cycle. Molten material is distributed to each cavity in the mold from the runners. Because the cavity is generally not heated, the design is called a cold-runner mold, and material in the cold runner hardens or cures with the part and is then removed from the part and discarded as scrap or in the case of stable thermoplastic formulations, sent to be recycled in a later molding run after each cycle. Cold runner systems are generally used for applications in which materials are inexpensive or when use of recycled material is acceptable, as they are less expensive than hot runner systems. However, materials cannot be reprocessed indefinitely, especially if thermally labile, and if thermoset materials are used in cold runner molds, the material must be discarded.

Hot runner systems use a heated manifold that is fed by the injection nozzle and keeps the material molten in the runners in the mold frame outside the plane of the cavity. The molten material enters the cavity from the runners via valve-gates or tips, and there is no scrap, so costly raw materials losses are minimized. Only the material in the cavity cools and hardens on each cycle, and molten material for the next cycle is forced into the cavity from the hot runners as fresh material is pumped into the hot manifold from the barrel nozzle. The fact that material remains continuously molten in the mold means that thermally sensitive materials can be subject to degradation, and the volume of hot runners should be kept as low as possible (a few cavity volumes at most) to ensure labile material does not have a long residence time in the molten state.

PHARMACEUTICAL PRODUCTS BY INJECTION MOLDING

Simple and complex shapes can be produced by IM, and as such, the process is used to prepare a wide variety of plastic medical device parts from caps, seals, closures, syringes, valves, and even implants. All of these require formulation of polymers with a range of additives, such as colorants, antioxidants, fillers, and plasticizers. Many of the compounds are pre-prepared by hot-melt extrusion, pelletized, and the pellets fed to the injection molder to form the part. Whereas the halves of a gelatin capsule that can be filled with API formulation are traditionally made by hardening a gelatin solution coated on a shaped metal pin by dipping it a into gelatin solution, IM can be used to prepare capsules, for example, the FlexTabTM technology that Capsugel acquired in 2011.

More recently, IM has been used to directly incorporate APIs into shaped plastic parts, and hence used to prepare drug products. The majority of drug products prepared by IM are drug-eluting devices (DED); however, even more recently, IM has been used to prepare solid oral dosage forms (SOD). IM offers the product developer novel delivery features, specific shaped-part preparation capability, and potential for life-cycle management of APIs. Commercial DED prepared by IM include intravaginal rings (IVR), and several such devices on the market made of silicones manufactured using a RIM process. Examples of such IVR are FemRing®, Estring®, and Progering® for hormone replacement therapy, vaginal atrophy, and contraception, respectively. These are core-sheath reservoir devices in which a drug-loaded silicone core is coated with a drug-free silicone sheath to regulate the rate of release of API from the device, yielding virtually zero-order (constant) release kinetics. The sheath is put over the core in a second injection molding process, making manufacturing quite complex. The International Partnership for Microbicides (IPM) working with Karl Malcolm and David Wolfson at Queens University, Belfast, has leveraged silicone technology in the development of a simpler IVR containing the non-nucleoside reverse transcriptase inhibitor dapivirine that does not have a rate controlling membrane.1 This IVR is a device to protect women from HIV transmission during sexual intercourse with an infected partner, and is slated to start Phase III clinical trials in 2012.

The RIM process requires the API and any other excipients to be suspended in the silicone liquids prior to injection (silicones are poor solvents so all added materials are suspended). Challenges arise from aggregation and settling of particulate materials in these fluids, which can cause inhomogeneities and nozzle blocking.

Particle Sciences uses IM in the development of EVA and polyurethane DED for a variety of clients.2,3 EVA and polyurethanes are thermoplastic polymers, and APIs and additives can be co-mixed uniformly with it prior to IM using hot-melt extrusion to yield pellets that are stable and can be used right away or stored for later IM processing. IVRs are developed first at laboratory scale using a bench-top molder, and successful formulations are then scaled to larger molding units for clinical and then commercial process development. The in vitro release of dapivirine from an EVA IVR made by molding dapivirine-loaded pellets (1.3% w/w API) in a mold with a torroidal cavity is shown in Figure 4 orange markers), along with the drug-release profile fitted using a proprietary predictive model (blue line) showing excellent fit to the data. The diffusion coefficient of dapivirine in EVA can be determined from these plots, which in turn allows the prediction of release profiles from EVA IVRs of different strengths to be made.

The shape of the curve is typical of release from monolithic devices that do not have release-rate controlling membrane, such as the aforementioned silicone IVR, according to Fick’s law for diffusion modified for the geometry of the part.4 Such products are appropriate when a high release on day 1 of use compared to later time points is acceptable or desired.

Very small shaped parts can be made by IM. For example, punctual plugs – smallpolymer pieces shaped to fit into the orifice through which tears drain (the puncta) – are used in the treatment of dry eye and other diseases of the eye. They can be pure polymer or medicated with API. In either case, they are prepared by micro-injection molding. Researchers at the University of Ghent in Belgium, have used IM to prepare API-loaded tablets for oral sustained release.5 For example, metoprolol tartrate (MPT) was formulated into a mixture of polyethylene oxide (PEO) and ethyl cellulose (EC). The formulations were injection molded into biconvex tablets using a Haake MiniJetTM lab-scale injection molder, and the in vitro release profiles of the MPT/PEO/EC tablets were compared to  compression molded tablets. The workers found a more sustained-release from the injection molded tablets. The Danish pharmaceutical company Egalet developed a two-step IM process to prepare oral dosage forms. The first step involves molding an open-ended “tube” of non-degradable polymer into which a thermoplastic API/polymer formulation is molded in a second step.6 Drug is released by erosion from the open ends. The process is illustrated in Figure 5.

SUMMARY

Injection molding is a versatile process that has been in use in plastics processing for more than a century. More recently, it has been used in the pharmaceutical industry to prepare products from medical devices to complex controlled-release dosage forms for both oral and implantable routes of administration.

REFERENCES

1. Malcolm RK, Edwards KL, Kiser P, Romano J, Smith TJ. Advances in microbicide vaginal rings. Antiviral Research. 2010;88[Suppl 1, S30-9].
2. Clark MR, Kiser PF, Loxley A, McConville C, Malcolm RK, Friend DR. Pharmacokinetics of UC781-loaded intravaginal ring segments in rabbits: a comparison of polymer matrices. Drug Delivery Translational Research. 2011;1(3):238-46.
3. Loxley A, Gokhale A, Kim Y, McConnell J, Mitchnick M. Ethylene-vinylacetate intravaginal rings for zero-order release of an antiretroviral drug. Poster presented at the CRS annual meeting in NYC; 2008.
4. Siepmann, Siepmann. Modeling of diffusion controlled drug delivery. J Controlled Release. (2011) in press.
5. Quinten et al. Development and evaluation of injection-molded sustained-release tablets containing ethylcellulose and polyethylene oxide. Drug Development and Industrial Pharmacy. 2011;37(2):149-159.
6. See http://www.egalet.com/index.dsp?area=32.

Dr. Andrew Loxley is Director of New Technologies at Particles Sciences Inc., a contract research organization in Bethlehem, PA, specializing in pharmaceutical formulation development. He leads a variety of p rojects, based on novel and proprietary nanotechnologies and combination devices, in fields from HIV vaccine and microbicide development, to gene-silencing SiRNA delivery. Prior to joining Particles
Sciences, he led development efforts in nextgeneration lithium ion batteries at A123 Systems Inc, electrophoretic displays at EINK  orp., and emulsion polymers at Synthomer Ltd. British-born, he earned his BSc in Chemistry from the Univeristy of Sussex and his PhD in Physical Chemistry focusing on microencapsulation from the University of Bristol.

Brett Braker is a Formulator at Particle Sciences, focusing on the development of drug-eluting devices. He earned his BS in Plastics and Polymer Engineering Technology from Pennsylvania College of Technology.