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Enhancing Dissolution of Poorly Soluble Drugs through Jet-Milling – Courtesy (PharmTech)
Formulation Discussion
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Mechano-chemical activation (MCA) is a process in which mechanical energy is transferred to a solid material during grinding. The accumulated energy (ΔE) generates a thermodynamic transition from a stable to a metastable, high energetic structure of the material. To revert to the thermodynamically stable form, it is necessary to release the excess energy. The energy relaxation can occur through the following three mechanisms: heat, plastic deformation, or rupture of chemical bonds (mechano-chemical reaction) (see Figure 1).

Initially, the energy relaxation can occur by heat generation. When the stress field reaches a critical level, relaxation may take place through material comminution with a consequent increase of the surface area. Then, when the particle size reaches a critical level at which new cracks cannot be formed, plastic deformation of the crystals may occur, generating randomized or regular crystal defects. As a result of this relaxation, polymorphic and/or amorphous structures are generated. By applying a higher energy level and by increasing the process time, the relaxation gives rise to chemical bond ruptures in the material (1).

Crystal transformation to the amorphous phase can be explained on the basis of two leading theories—mechanical and thermodynamic destabilization. According to the first theory, crystal lattice collapse occurs due to too high an harmonicity of lattice vibrations because of mechanical stress. The second theory affirms that crystal defects increase up to a critical threshold beyond which the amorphous phase is thermodynamically more stable than the crystal one (2). If crystal defects are not randomized but follow a particular order, a metastable polymorph structure is generated. Experimental evidence indicates that chemical interactions between solids occur in the contact areas between the particles not involving the entire volume of the solid materials or their entire surface (3). Regardless of the formation mechanism, because both the amorphous and the polymorphic forms obtained through mechanical activation are thermodynamically unstable, the problem arises as to how to stabilize the activated material and preserve its high reactivity (2,4).

Figure 1: Schematic representation of the mechano-chemical activation (MCA) process. ΔE is accumulated energy.

Mechano-chemical activation as a drug delivery platform
The first description of the mechano-chemical activation applied to drugs dates back to 1977, where a co-grinding process of drugs with microcrystalline cellulose (5) and mixtures of drugs with 1-4 glucan polymer (6) were described. Since then, several studies have been carried out on the co-grinding process, even though focused on the performance of the excipients used and on their compatibility with selected drugs rather than on the evaluation of the equipment used and the process parameters applied. The described approach was developed as an alternative method for obtaining solid dispersed systems of poorly soluble drugs. In particular, the activated drug, showing better dissolution rate, could be stabilized by the addition of a pharmaceutical polymer in the grinding mixture. The interactions between the drug and the added stabilizer are substantially based on hydrogen and Van der Waals bonds, which would increase the lifetime of drug metastable states in the final drug/polymer composite (2,4).

According to literature, the following polymers are generally employed in a MCA via co-grinding process: silica gel (7), sodium starch glycolate (8), crospovidone (9), and especially beta-cyclodextrin (10). However, the MCA process, as described in the literature, has been based on the use of “high energy” mechanical mills (e.g., ball, planetary, vibration, or centrifugal mills) using high-density material (e.g., zirconium, steel) as the grinding media. These grinding media have been considered essential to develop sufficiently high energy to allow the interaction of the active ingredient with the stabilizer and to promote the “activation” of the powder mixture and the formation of a supra-molecular structure.

In MCA, through the drug/polymer co-grinding, the following physicochemical phenomena occur–particle size reduction, amorphization, and drug complexation or its inclusion within the polymer. The result of the MCA process is a pharmaceutical composite with improved physico-technological properties and an increase in both dissolution rate and physico-chemical stability.
For Biopharmaceutics Classification System (BCS) Class II drugs (high permeability, poor solubility), the dissolution in the gastrointestinal tract is the rate-limiting step of the absorption process. Increasing the dissolution rate could lead to an enhancement in bioavailability and therapeutic effect (11). Considering the huge number of BCS Class II drugs, investing in innovative solubilization strategies is of great economic interest to the pharmaceutical industry, including generic-drug manufacturers.
Approximately 70% of new chemical entities fall into the BCS Class II category (12), hence requiring application of appropriate pharmaceutical technologies during dosage-form development to achieve an improved biopharmaceutical profile. For this class of drugs, the dissolution rate is the key parameter for the in-vitro evaluation of delivery systems.
The dissolution rate of solute particles is described by the Noyes Whitney equation where:

A = surface area of solute particles
C = concentration of solute particles in the bulk dissolution medium
Cs= concentration of solute particles at the boundary layer
D= diffusion coefficient
L= diffusion layer thickness

Based on this equation, two approaches are generally applied. Firstly, the dissolution rate of poorly soluble drugs can be improved by increasing the surface area (A) through particle size reduction. The most widely used method, in this case, is micronization because of its robustness, safety, and the reduced cost of the process. Another approach is based on increasing the Cs parameter (i.e., by increasing the drug concentration inside the diffusion layer by physicochemical and/or solid state modifications). The most common methods are: complexation with solubilizing agents (e.g., cyclodextrin [10]), use of self-emulsifying drug delivery systems (13) and formulation of solid dispersions in water-soluble carriers (14).

JetMCA technology
JetMCA is a new technological approach that combines increasing both the surface area (through particle size reduction) and the drug concentration in the diffusion layer (through drug amorphization) by the use of a modified fluid-jet mill. The resulting activated drug/stabilizer composite is a solid dispersion that is manufactured through a dry process, without the use of any grinding media.

Table I shows the advantages of this technology, compared with other well-established processes used in the manufacture of solid dispersions. In particular, jetMCA does not require any heat application and is therefore suitable for thermolabile drugs. No solvents are required, making it a one-step process. JetMCA offers a straightforward technique for the preparation of solid dispersions.
For the manufacture of solid dispersions by jetMCA, modifications of a traditional fluid-jet mill equipment are required to achieve MCA of drug/stabilizer mixtures. In particular, the residence time of the drug/stabilizer powder mixture in the milling chamber is to be increased to reach a sufficiently high level of mechanical energy for material activation. A simplified scheme of a fluid-jet mill that has been modified to allow the MCA process is shown in Figure 2.

Figure 2: Diagram showing a fluid-jet mill modified to allow long co-grinding times and mechano-chemical activation.

The compressed gas is fed through the pipe (a) inside the milling area (b) located in the mill chamber (c). The powder mixture is loaded into the mill and then pushed by the gas stream through a static grader (d), which allows particles with a predetermined size to pass through. The particles exiting from the grader can then be reintroduced into the grinding chamber (b) through a recirculation system, which includes a separator filter (e) and pipelines connecting the bottom part of the separator filter to the powder pumping device (f), which allows a continuous and regular powder transfer. The separator filter is cleaned with a flow of pressurized gas fed through the second pipe (g). An absolute filter (h) ensures that no leak of fines occurs during processing.

Table I: Comparison of Jet-MCA with hot-melt extrusion and spray drying.
Technology Process Key Features
Jet-MCA Dry blending of API and polymer No solvent use
No heat application
Jet milling with a recirculation system Particle size reduction
No risk of mechanical contamination
Mechano-chemical activation
Generation of an API-carrier composite
Hot-melt extrusion API dissolved into a molten polymer Limitation due to high temperature, affecting API stability
Critical equipment parameters for dispersion homogeneity
Extrusion of the molten mixture Minimum batch size relatively large (cost and risk in early
development)
Extrudate cooling and milling
Spray drying API and polymer dissolved into a solvent Use of solvents (cost, safety, environment)
Broad applicability to API
Spraying the solution in a drying chamber High capital and operating costs
Fine particle collection

Application of jetMCAto a poorly soluble drug
Dehydroepiandrosterone (DHEA), a BCS Class II compound, was used as the model drug. DHEA was chosen based on its physicochemical characteristics (i.e., poor water solubility [63.5 mg/L] and good permeability). Crospovidone was used as a stabilizing polymer. The aim was to demonstrate application of the JetMCA technology in the manufacture of a solid dispersion by suitably modified fluid-jet mill equipment.

There are several papers in the literature reporting on the preparation of solid dispersions of DHEA. The approaches used include adsorption on crosslinked polymers with the use of solvents (15), α-cyclodextrin complex formation (16), and activation of a ternary mixture by mechanical vibrational milling (17).

In this study, a formulation parameter (drug/stabilizer weight ratio) and a few operational parameters (gas pressure, classifier speed) were considered to assess the process feasibility and, in particular, MCA of DHEA/crospovidone mixtures. The results obtained with a 1:3 weight ratio between DHEA and crospovidone are presented.

The DHEA/crospovidone mixture was fed through a Venturi system into the milling chamber of the jetMCA equipment (see Figure 2). The co-micronization process was carried out up to 3 hours; samples were taken at 60 min, 120 min, and 180 min of recirculation and analyzed by differential scanning calorimetry (DSC). The thermogram in Figure 3 shows a progressive reduction of the DHEA enthalpy of fusion, which can be attributed to a decrease of its crystallinity. The sample taken after 3 hours presents 98% amorphization. The degree of amorphization is calculated using as 100% reference, the enthalpy of fusion peak of the DHEA in the 1:5 physical mixture at zero time.

Figure 3: Differential scanning calorimetry thermogram of the dehydroepiandrosterone/polyvinylpyrrolidone (DHEA/PVP) 1:3 composite. DHEA/PVP 1:3 physical mixture (red), activated drug composite after 1 hour (blue), 2 hours (green), and 3 hours (violet) of recirculation in the jetMCA equipment.

The decrease of DHEA crystallinity was confirmed by powder x-ray diffraction (PXRD) analysis, which showed a reduction of the diffraction peaks intensity in favor of the typical path due to the presence of amorphous material.

To assess the in-vitro performance of the activated composite, dissolution testing in simulated gastric fluid without enzymes (at pH 1.2 and 37 °C) was carried out on the DHEA/crospovidone samples (see Figure 4) prepared by applying different process conditions.

Figure 4: Dissolution profiles in simulated gastric fluid pH 1.2 at 37 °C. Dehydroepiandrosterone/polyvinylpyrrolidone (DHEA/PVP) 1:3 physical mixture (blue), activated drug composite after 1 hour (red), 2 hours (green), and 3 hours (violet) hours of recirculation in the jet-MCA equipment.

The amount of DHEA released in 1 hour from the DHEA/crospovidone composite, with a weight ratio 1:3, was double as compared to the corresponding physical mixture at zero time. A significant reduction of the residual crystallinity of the drug, proportional to the process time, was observed and quantified. This finding was considered as the preliminary indication of MCA. In-vitro studies confirmed this activation showing an increase in the solubilization rate and solubility of the drug in both sink and supersaturation conditions (18).

Conclusion
MCA of physical mixtures of a poorly water-soluble drug and a suitable pharmaceutical polymer has been described in the past, using mainly high-energy mechanical mills that have proven effective in improving biopharmaceutical properties of the mixture, in terms of drug amorphization and dissolution profile. This technological approach, however, presents some constraints because of the impact of grinding media onto the powder mixture, with possible drug contamination and the long processing time required to achieve the activation.

By modifying a jet mill device, it was possible to carry out a MCA process without the use of any grinding media, but by applying a recirculation system to increase the residence time of the powder mixture in the milling chamber.

Activation was demonstrated on a physical mixture of DHEA (the model drug) and crospovidone (as a polymer able to interact with the drug and stabilize the activated composite). In particular, the results of DSC analysis and PXRD showed a decrease of drug crystallinity, while the dissolution rate of the activated composites was significantly increased when in-vitro studies were performed.

References
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6. Y. Nakai, S. Nakajima, and K. Sugiyama, “Method of increasing the rate of solubility of materials of low solubility,” patent US4036990, July 1997.
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12. S. Stokbroekx, “Formulation Effects on Drug Absorption,” EUFEPS and COST B25 Conference on Bioavailability and  Bioequivalence: Focus on Physiological Factors and Variability (Athens, Oct. 1-2, 2007).
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18. F. Carli, P. Iamartino, M. Leone, “Drug/Carrier Inclusion Composites Prepared by a Mechanochemical Activation Process Using High-Energy Fluid-Jet Mills,” patent WO2013110789, August 2013.

About the Authors

Piero Iamartino, MSc, is R&D manager,Micro-Macinazione S.A. Salvatore Mercuri, PhD, is R&D senior scientist Micro-Macinazione S.A.

Article Details
Pharmaceutical Technology
Vol. 39, No. 2
Pages: 34-38
Citation: When referring to this article, please cite it as P. Iamartino and S. Mercuri, “Enhancing Dissolution of Poorly Soluble Drugs through Jet-Milling,” Pharmaceutical Technology 39 (2) 2015.



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