Hot melt extrusion has been widely used as a processing method for many purposes, including formation of a solid molecular dispersion to increase the bioavailability of poorly soluble drugs.1 Analytical tools and techniques can greatly reduce time and improve success rates in development of hot melt extrusion formulations. In the formulation development stage, analytical characterization of molecular dispersion simplifies the process to compare and contrast different hot melt formulations. In the scale-up phase, analytical characterization techniques ensure similar solubility enhancement occurs on larger extrusion equipment as with the lab-scale equipment used for formulation development.
Analytical Techniques for HME Formulation Development
With the advent of smaller extrusion equipment, melt extrusion processing of drug substances can now be performed on the gram scale. Solid molecular dispersions of nifedipine, nimodipine, and itraconazole have been successfully produced using melt extrusion technology.2-4 Analytical characterization of dispersions prepared by melt extrusion is necessary to assess its physical and chemical properties and performance in the final drug product. Interpretation of the analytical data can be challenging. A ep-wise approach for characterizing a molecular dispersion simplifies the process to compare and contrast different formulations. Testing a formulation at the next step only occurs if acceptable results are obtained.
Microscopy, thermal analysis, spectroscopy, and non-sink dissolution test methods are frequently used to characterize formulation candidates and provide product performance and stability information.5 Characterizing the dispersion formulations in three steps can reduce evaluation and development time. The first step is to evaluate the quality of a molecular dispersion prepared by melt extrusion using microscopy (light or scanning electron microscopy) and thermal analysis methods (differential scanning calorimetry). 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. Crystals can seed formation of other crystals, and ultimately a reduction in product performance. The presence of a small number of crystals may be due to exceeding the carrying capacity of the polymer. A formulation with a lower drug loading may provide an improved molecular dispersion.
Modulated differential scanning calorimetry (mDSC) is used to qualitatively confirm that the dispersion has a single glass transition temperature (Tg) and identify a value for the Tg, and the lack of a melting point corresponding to the drug substance. It is important to run a physical blend of the formulation as a control. Often, the drug may dissolve into the polymer as the temperature is increased during the test
The second step completes the assessment of dispersion quality using methods to determine crystallinity, eg, x-ray powder diffraction (XRPD) and 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. Again, it is important to analyze a physical blend of the formulation. Formulations with low drug loadings may be below the sensitivity of the method to detect crystals. Non-sink dissolution testing evaluates each dispersion formulation for enhancement and sustainability of supersaturation over the crystalline drug form, and can be used to rank-order formulations.
The third step encompasses tests to evaluate physical and chemical stability of the dispersion, generally by mDSC and high performance liquid chromatography (related substances). DSC is used to analyze how the Tg changes as a function of humidity. This test is used to rank-order formulations based on the value of the Tg at a constant equilibrated humidity, such that the highest Tgformulations would have the best predicted physical stability for miscible mixtures of drug and polymer. The related substance test by HPLC determines, under the processing conditions used to manufacture the dispersions, no chemical degradation of the drug substance occurred.
Formulation Development Case
An example of the third step analytical characterization approach is presented further. Melt extrusion of a poorly water-soluble drug substance was evaluated in two different polymers (EUDRAGIT E 100 and polyethylene oxide) at two different drug loadings. DSC analysis of the neat drug, neat EUDRAGIT E 100, neat polyethylene oxide (PEO), and the four formulations is presented in Figure 1. Melting points associated with the drug substance are absent from the formulations. Melting points corresponding to PEO are present, and depressed, in the two PEO formulations, indicating the drug is plasticizing the polymer. A single glass transition was observed in the two EUDRAGIT E formulations.
Light and scanning electron microscopy was performed on the neat drug (needle shaped), the polymers and four formulations (data not shown). Crystals were absent in the EUDRAGIT E formulations, but crystals were visible in the PEO formulations. The crystals in the PEO formulations were consistent (size and shape) with the polymer, reinforcing the presence of the PEO melting transition observed in the DSC results.
All four formulations were advanced to Step 2 testing. X-ray powder diffraction of the neat drug and the four formulations are presented in Figure 2. Physical blends of each formulation (data not shown) indicated the presence of crystalline peaks associated with the drug substance, and peaks associated with PEO in those respective formulations. Crystalline peaks associated with the drug substance are absent in the melt extruded formulations.
Non-sink dissolution testing of the neat drug and the four formulations is presented in Figure 3. All four formulations achieved a supersaturation of the drug substance within the 90-minute time frame of the test. Samples were also taken at 4-, 8-, 24-, and 36-hour time points to assess the sustainability of supersaturation (data not shown). Three formulations maintained supersaturation at the 8-hour time point. All four formulations were unable to sustain supersaturation at the 24-hour time point.
Three formulations were advanced to Step 3 testing. HPLC analysis of the molecular dispersion prepared by melt extrusion demonstrated the maintenance of chemical stability. Degradants were not observed in the three formulations. The formulations were also placed into a stability chamber at 40°C and 75% for 4 weeks in open containers. The samples were analyzed by DSC at 1-, 2-, and 3-week time points (data not shown). The EUDRAGIT E formulations maintained the glass transition temperature observed initially, indicating a stable formulation. The PEO formulation adsorbed a significant amount of water and softened, but the presence of a thermal event associated with the drug substance was not observed. A thermal event associated with the boiling point of water was observed.
Melt extrusion processing is a technique widely used to form solid molecular dispersions of a drug in a polymer to enhance bioavailability. Extrusion experiments and analytical tests may be performed on a small scale to conserve costly active pharmaceutical ingredients (API). A step-wise approach to characterizing formulation prototypes using microscopy, thermal analysis, spectroscopy, non-sink dissolution testing, and chromatography can be used to rapidly rank order formulations.
Analytical Techniques for HME Process Scale-Up
Formulation development using hot melt extrusion is generally performed using small, laboratory equipment. Scale-up of these developed formulations by achieving similar properties of the dosage forms is always a challenge in pharmaceutical industry. There is limited information available in the literature for scale up of solubility-enhanced formulations prepared by melt extrusion processing. Analytical characterization and techniques are critical in the scale up of these melt extruded solid dispersions in order to ensure similar products are produced, specifically in obtaining similar solubility enhancing effect.
When attempting to achieve similar solubility for a formulation on a large extruder to that of the lab scale, the first step is to match process energies between the extruders, both mechanical and thermal. Mechanical energy influences the degree of mixing achieved in the process, and thermal energy determines the amount of heat the formulation experiences in the process. Matching energy input of the extruders ensures good mixing without degrading the formulation.
Computer-aided process simulation is used to match energies between the small and large extruder. This requires thermodynamic and rheological characterization of the formulation. The simulation provides an initial screw design and process conditions for the larger extruder that provides similar mechanical and thermal energies to the small extruder.
Once initial a screw design and process conditions are established for the large extruder, extrusion trials provide samples that can be analytically characterized and compared to the original samples. Iterative trials to fine tune process conditions may be required to achieve optimal results.
Process Scale-Up Case
A stable, solid dispersion of EUDRAGIT E/nifedipine and EUDRAGIT NE 30 D formulation was required to be scaled up from an 18-mm twin screw extruder to a 27-mm twin screw extruder. Consistent physical and chemical properties of the scaled up solid dispersion were required.
Different drug loadings (10%, 20%, and 30% nifedipine) were extruded with EUDRAGIT E PO/NE 30 D (90%:10% dry polymer). EUDRAGIT E PO and EUDRAGIT NE 30 D were extruded in a first step to prepare a pre-blend and cut into granules. Nifedipine and the granular polymer blend were fed with separate doses into either an 18-mm or 27-mm co-rotating twin-screw extruder (Leistritz, Nuremberg, Germany).
Scale-up parameters were calculated with software to determine all important parameters. Scale-up parameters on the 27-mm extruder were based on the process parameters from the 18-mm extruder. Screw configuration in both extruders consisted of conveying and mixing elements. The screw speed of the 18 mm was set to 140 rpm. Based on the mass throughput, the output of the 27-mm extruder was calculated to be 100 rpm. Screw configuration on both extruders were similar. The melt was cooled as a strand on a conveying belt and subsequently cut into cylindrical granules. The granules were milled prior to analysis.
Visually, the extrudates were completely transparent, indicating a transformation of crystalline nifedipine into an amorphous state. XRPD analyses for extrudates were performed on an X´Pert Pro (PANalytical) using an X´Celerator as detector. The instrument is equipped with a Cu tube as X-ray source. Each diffractogram was recorded between 4°C and 74°C (2θ). Crystallinity was not observed.
Dissolution testing was performed under non-sink conditions using a USP apparatus II in 900-ml 0.1N HCl pH 1.2, 100 rpm. Samples equivalent to 45-mg nifedipine were analyzed.
The extrudates were stored in HDPE bottles at 40°C/75% relative humidity. Formulations prepared with 10% and 20% drug loading were stable over 3 months. The formulation containing 30% drug loading demonstrated a decrease in dissolution rate of 20% to 25%.
Initially, a faster release rate of the extrudates prepared with the 27-mm extruder was observed. The faster release rate was due to the differences in granule particle size. The granules from the 27-mm extruder were smaller than the granules prepared with the 18 mm. The formulation with 20% drug loading demonstrated a slight re-crystallization after dissolution testing. This observation can be attributed to small crystals present in the extrudate that could not be detected by XRPD, seeding re-crystallization.
XRPD and dissolutions studies were used to confirm formulations with EUDRAGIT E/NE 30 D containing different loadings of nifedipine demonstrated an increase in solubility and a stabilized dissolution profile. 10% and 20% drug loading were stable up to 3 months at accelerated conditions. Trials on the 18-mm and 27-mm extruder led to similar dissolution behavior of nifedipine from the extrudates. This study demonstrated that scale up of a solubility-enhanced formulation containing EUDRAGIT from an 18-mm to a 27-mm extruder could successfully be performed. EUDRAGIT polymers proved to be suitable carriers for storage stable solid dispersions, enhancing the solubility of poorly soluble drugs.
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Managing Director, Foster Delivery Science
Email: [email protected]
About Foster Delivery Science:
Foster Delivery Science is a contract research and manufacturing firm specializing in hot melt extrusion (HME) of active pharmaceutical ingredients (APIs) and polymers for highly regulated applications, including oral dose tablets, transdermal film, and bioresorbable implants. Services include formulation, feasibility, process development, and production in an ISO 8 cGMP clean room environment.