A significant number of new active pharmaceutical ingredients (APIs) are poorly water soluble and cannot be formulated and processed with traditional aqueous methods. Hot melt extrusion (HME) has become an effective solubilization tool in improving the dissolution rate of poorly water soluble drugs to enhance their bioavailability after oral administration1. These crystalline hydrophobic drugs can be dispersed in hydrophilic polymers using HME to manufacture amorphous solid dispersions.
Although relatively new to the pharmaceutical industry, melt extrusion is a widely used technology in the plastics industry. It is a solvent free process that achieves solid molecular dispersions by a melt blending process, in which the API is dispersed and or dissolved into a polymeric matrix. The resultant solid dispersion is extruded into strands and then cut or milled into a dense granular or pelletized form. While suitable for injection molding tablets or extruding into film or fiber delivery forms, the granules or pellets often require additional milling prior to tablet pressing.
Initial studies indicated that adding foaming agents to the extrudate during the HME process can improve processing of high melt viscosity materials, enhance milling of pellet for tablet manufacturing, and in some cases increase API release rate.
HME Process & Analytical Methods
HME commonly utilizes twin screw mechanical mixing of constituents to achieve dispersion of the API, polymers and excipients. Each formulation produced by hot melt extrusion has a “process energy” comprised of mechanical and thermal energies that ensure homogenous mixing without degradation of the API or excipients.
While mechanical energy influences the degree of mixing, thermal energy determines the amount of heat sustained by the formulation throughout the blending process. A number of variables are used to optimize the process formulation, including but not limited to, barrel and screw designs. Extruder barrels are zoned in sections which are individually heated and cooled depending on the formulation process parameters. Extruder screws are individually constructed with components that assist in melting (via shear forces) and convey material through the barrel, while mixing and homogenizing the formulation.
HME formulations are often characterized in a sequential fashion to ensure desired outcomes. Since dispersion of the API in the polymer matrix is critical, the first step is assessing dispersion quality using microscopy (Light or SEM) and thermal analysis methods (DSC). Microscopy is used for a visual assessment of the dispersion to detect the presence of drug crystals on or within the dispersion, and is usually the most sensitive method to identify crystals. DSC is used to quantitatively confirm that the dispersion has a single glass transition temperature (Tg) and identify a value for the dry Tg.
This is followed by a complete analysis of dispersion quality using crystallinity determination methods (e.g., x-ray powder diffraction [XRPD] or Raman spectroscopy) and evaluates performance using a non-sink dissolution test. XRPD or Raman can be used to identify the presence of crystals within the sample. The non-sink dissolution test evaluates each of the dispersions for enhancement and sustainability of supersaturation over the crystalline drug form.
Finally, the solid dose is evaluated for physical stability using DSC and chemical stability by related substances. DSC can be used to analyze how the Tg changes as a function of humidity. This test is used to assess formulations based on the value of the Tg at a constant equilibrated humidity, such that the highest Tg formulations would have the best predicted physical stability for miscible mixtures of drug and polymer. The related substance test is to evaluate that, under the processing conditions used to manufacture the dispersions, no chemical degradation of the drug substance occurred.
The APIs can be mixed with a variety of polymers at high temperatures to manufacture solid dispersions in different shapes2. As such, polymer processing technologies such as fiber and film extrusion, or injection molding of shapes can be employed for a variety of delivery forms. With appropriate post extrusion processing equipment, such forms can be produced directly from the HME process.
Tablet forming, a common delivery form for oral dose pharmaceuticals, often requires additional milling of the extrudate to produce a powder sufficient for forming tablets.
Foamed Hot Melt Extrusion
The pharmaceutical industry continues to investigate applications of HME technology in developing various drug delivery systems such as granules, pellets, tablets, transdermal systems, and ophthalmic implants3. Although HME is an attractive process for manufacturing pharmaceutical formulations, processing of high melting APIs and high glass transition polymers is a challenge due to high melt viscosity. Permanent plasticizers such as triethyl citrate, tributyl citrate, dibutyl sebacate, and surfactants have been investigated in order to reduce the melt viscosity during the HME process4. Inclusion of these plasticizers however not only adds extra weight to the formulation but may also increase the possibility of crystallization of amorphous APIs.
Recently, super critical carbon dioxide (SCCO2) is being used as a temporary plasticizer to reduce the glass transition of the polymers during HME, without being present in the final formulation. SCCO2 acts as a molecular lubricant by increasing the free volume and reducing the chain entanglement after getting absorbed between the polymer chains5. Further, such SCCO2 induced foam HME-product becomes more suitable for milling.
Foamed hot melt extrusion (FHME) has been considered a second generation HME technology to facilitate processing, improve the milling efficiency of the extrudate, and further increase the API release rate. In an initial investigation, the release rate of poorly soluble drug Nifedipine was improved by hydrophilic polymer *Eudragit® EPO using Foam HME.
Experimental Methods for FHME
In an initial study, Nifedipine was selected as poorly water soluble BCS class II API and Eudragit EPO was chosen as a hydrophilic polymer. The drug was mixed with the polymer to prepare physical mixtures with following ratios.
- EPO 70: API 10: Talc 20
- EPO 89: API 10: Talc 1,
- EPO 89: API 10: Foamed
These physical mixtures were extruded at 100 rpm. SCCO2 was injected into the extruder during extrusion. Temperature profiles along the screws were carefully set to assure optimal mixing and prevent thermal degradation. An appropriate screw configuration was selected to avoid the high pressure CO2 from escaping the extruder through the feeder.
Differential scanning calorimetry (DSC) of milled HMEs was performed to confirm the transformation of crystalline API into its amorphous form. The samples were sealed in aluminum pans and heated to 200°C.
A dissolution study was performed using USP apparatus II at 37.5°C, and 50 rpm in 0.1N HCl for 2 hours.
The melting endotherms of Nifedipine were not detected in the HME samples that confirmed formation of amorphous solid dispersions of Nifedipine in Eudragit EPO. Further, single glass transition temperatures were observed suggesting formation of molecular dispersions (Figure 1).
The dissolution rate and supersaturation of Nifedipine were significantly improved with the increase in polymer concentration as shown in Figure 2. Like un-foamed HME, Nifedipine was entirely released within 20 minutes from the foamed HME. Moreover, the dissolution rate of foamed HME was faster than the un-foamed HME, given the same excipient-drug ratio (blue and green curves). Two foamed samples are significantly different in terms of dissolution rate and the final degree of supersaturation in dissolution medium (blue and red curves), which is probably due to the different excipient-drug ratio or addition of talc.
Supercritical carbon dioxide induced foaming was successfully used in improving the processing of HME technology. The foamed HME molecular solid dispersions were found to be amorphous. The release rate of Nifedipine could be tailored due to foaming. The study demonstrated the unique advantages of using CO2 as a plasticizer for HME.
*Eudragit is a registered trademark of Evonik Industries
- Repka MA, Battu SK, Upadhye SB, Thumma S, Crowley MM, Zhang F, Martin C, McGinity JW 2007. Pharmaceutical applications of hot-melt extrusion: Part II. Drug Dev Ind Pharm 33(10):1043-1057.
- Repka MA, Majumdar S, Kumar Battu S, Srirangam R, Upadhye SB 2008. Applications of hot-melt extrusion for drug delivery. Expert Opin Drug Deliv 5(12):1357-1376.
- Crowley MM, Zhang F, Repka MA, Thumma S, Upadhye SB, Battu SK, McGinity JW, Martin C 2007. Pharmaceutical applications of hot-melt extrusion: part I. Drug Dev Ind Pharm 33(9):909-926.
- Ghebremeskel AN, Vemavarapu C, Lodaya M 2007. Use of surfactants as plasticizers in preparing solid dispersions of poorly soluble API: selection of polymer-surfactant combinations using solubility parameters and testing the processability. Int J Pharm 328(2):119-129.
- Verreck G, Decorte A, Heymans K, Adriaensen J, Cleeren D, Jacobs A, Liu D, Tomasko D, Arien A, Peeters J, Rombaut P, Van den Mooter G, Brewster ME 2005. The effect of pressurized carbon dioxide as a temporary plasticizer and foaming agent on the hot stage extrusion process and extrudate properties of solid dispersions of itraconazole with PVP-VA 64. Eur J Pharm Sci 26(3-4):349-358.