Dissolution of Solid Dispersions of Ibuprofen Studied by Fourier

Chapter 13

Dissolution of Solid Dispersions of Ibuprofen Studied by Fourier Transform Infrared Imaging *

Downloaded by PURDUE UNIVERSITY on July 10, 2013 | http://pubs.acs.org Publication Date: March 9, 2006 | doi: 10.1021/bk-2006-0924.ch013

K. L. Andrew Chan and Sergei G. Kazarian

Department of Chemical Engineering and Chemical Technology, Imperial College, London S W 7 2AZ, United Kingdom Corresponding author: [email protected] *

The application of Fourier Transform infrared (FTIR) imaging using the macro attenuated total reflection (ATR)-IR metho dology to formulations of ibuprofen in poly(ethylene glycol) (PEG) enabled characterization of the distribution of both, polymer and drug, in the tablet. Visualization of the disso lution process upon contact of the tablet with flowing water has been demonstrated. The mechanism of dissolution and drug release for two tablet preparation methods (mechanical mixing and melt) have been compared using this spectroscopic imaging approach.

© 2006 American Chemical Society

In Polymeric Drug Delivery II; Svenson, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.

203


204 Improvement of the dissolution of poorly water-soluble drugs is often achieved via preparation of solid dispersions of the drugs in hydrophilic poly meric carriers. However, the issues o f stability, predictability, efficiency, and ultimately bioavailability of these formulations often hinder their adoption by pharmaceutical manufactures. (1-6) Therefore, a better understanding of the mechanism o f drug release from solid dispersion is needed to facilitate the opti mal design of such formulations. Despite numerous studies of solid dispersions, there is still a lack of understanding of processes that occur within these disper sions upon contact with dissolution media. (2) This situation is caused by the fact that conventional dissolution studies, such as described in the United States Pharmacopeia (USP), only analyze the drug concentration within the dissolu tion media as a function of time, without providing any insight into the complex processes that occur within the formulation. As a consequence, studies based on the conventional dissolution approach might result in erroneous conclusions and recommendations. For example, while it is generally believed that formulations of molecularly dispersed drugs within polymer carriers are required for the enhancement of dissolution rates, it was recently shown that these drugs can form a drug-enriched layer containing drug crystallites that actually hinder the overall drug dissolution. (7,8) Visualization o f processes occurring within formulations during dissolu tion, such as water uptake, drug diffusion, and polymer dissolution or erosion, are crucial for understanding the mechanism of drug release. This visualization has been achieved using magnetic resonance imaging (MRI), however, its spatial resolution and acquisition speed is limited. (9-11) A new experimental approach, based on Fourier Transform infrared (FTIR) spectroscopic imaging, has recently been developed to obtain more detailed insight into the processes within formulations upon contact with dissolution media. (7) Chemical speci ficity of FTIR imaging makes this a powerful method to analyze these processes. We have recently coined the term "chemical photography'* to describe this imaging method, which is based on the use o f the infrared array detector to simultaneously measure thousands of spectra from different locations. This approach has already been used to analyze in situ compacted tablets and to study pharmaceutical formulations under controlled humidity. (12-14) FTIR imaging in transmission mode was also applied recently to investigate drug delivery systems. (15) This FTIR imaging method is limited by the strong absorption of water in the infrared range, which requires either using D2O as the dissolution medium or preparing very thin samples. (15) Fortunately, the attenuated total reflection (ATR) sampling method allows overcoming this difficulty by measuring a relatively thin layer of the sample immersed in water. We have recently developed the methodology to image the dissolution of formulations in water using a diamond A T R accessory. (13,16) In a previous study, solid dispersions in P E G have been prepared via supercritical fluid impregnation or melting. (7,8)


205 Although supercritical fluid impregnation is a very promising method due to the lack of solvent residues and the use of near-ambient temperatures, it is still not broadly applicable. (17) Conventional techniques include mechanical mixing of drug and polymer or melting of polymer carrier to incorporate the drug. In this work we discuss the application of FTIR spectroscopic imaging to compare the effect of these two conventional preparation methods to image formulations in contact with flowing water.


Materials and Methods Mechanically Prepared Sample P E G powder ( M W 8000 Da, purchased from Sigma) with particle size bet ween 30-60 juim was prepared by grinding, followed by sieving of the P E G particles. The prepared powder was mechanically mixed with 20 wt% of ibu profen in a beaker. Sample Prepared by the Melt Method 20 wt% of ibuprofen was dissolved in molten P E G (MW 8000 Da) at 70 °C. The molten mixture was allowed to solidify at room temperature and then powdered with a spatula. Tablet Preparation 1 mg of the mixture was compacted in a newly developed tablet press, which was specifically designed for studying tablet dissolution. (13) The tablet press is integrated into a supercritical fluid analyzer (Specac, Ltd), allowing subsequent dissolution studies of the compacted tablet. A schematic presen tation of the tablet compaction cell is shown in Figure 1 (compaction mode). The tablet is compacted on one side of the diamond such that half of the imaging area will be exposed to an empty space. This arrangement allows studying the tablet disintegration into the dissolution medium. The advantage of this cell compared to our previous work (7) is that it allows studying the drug release under flow of water, which is more physiologically relevant. The design and the operational details of the tablet compaction cell are described elsewhere. (13) The powder was introduced into the compaction area and pressed by a piston, which was driven toward the compaction area by a screw anvil. The compaction force was controlled by a torque wrench with approximately 100 N of force applied (giving a hydraulic pressure of ca. 1400 bar).


206 Compaction mode

Dissolution mode


Diamond A T R Crystal Figure I. Schematic cross-section view of the compaction cell in compaction mode and dissolution mode. When the tablet is formed, the ring can be lifted using a spanner, allowing waterflow around the compacted tablet.

FTIR Spectroscopic Imaging A l l FTIR images were obtained with an IFS667s step-scan spectrometer (Bruker Optics) with a macro-chamber (IMAC™) extension. The diamond ATR-IR accessory (Specac, Ltd.) was placed in the sample compartment of the macro-chamber and aligned as described in a previous work. (16) A 64 x 64 focal plane array (FPA) detector was used to measure spectra. The distribution of absorbance of the characteristic absorption bands of ibuprofen and P E G in the measured area of the sample were used to construct corresponding chemical images. A low-pass filter was employed to reduce the measured spectral range to 1800-900 cm' in order to increase the acquisition speed and improve temporal resolution. A spectral resolution of 16 cm' was used with 5 coadditions giving a total scanning time of ca. 30 s. 1

1

Dissolution Study After compaction of the tablet, the compaction force was reduced to ca. 50 N to obtain a homogeneous contact between the A T R crystal and the tablet without deforming the tablet upon removal of the metal ring surrounding the tablet (see Figure 1, dissolution mode). Distilled water with a flow rate of 1 ml s' was pumped through the compaction cell using a Kontron 320 H P L C pump, and FTIR images were acquired at 1-minute intervals for the first 10 minutes and then at ca. 7-minute intervals afterward. 1


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Results and Discussion The advantages of FTIR spectroscopy for chemical analysis are based on the rich chemical information shown in IR spectra. The characteristic absorption band o f a component can be used to generate an image that represents the distribution of the particular component in the measured area of the sample. Reference spectra of crystalline ibuprofen and semi-crystalline P E G are shown in Figure 2. The absorption band of the carbonyl group vibration v(C=0) at 1710 cm" has been used to represent the distribution of ibuprofen, and the absorption band at 1100 cm" was used to plot the distribution of PEG. Chemi cal images are generated by plotting the integral absorbance value of these bands as a map such that the changing distribution of different components during dissolution can be monitored. The grey-scales of all images are adjusted such that direct comparison can be made between each component. 1


1

Figure 2. Reference FT-IR spectra of ibuprofen (black) and PEG (grey) in the fingerprint region measured with 4 cm' spectral resolution. 1

Dissolution of the Sample Prepared by Mechanical Mixing. The image of the compacted tablet acquired before the addition of water is shown in Figure 3 and indicated as time 0 min. The image shows a hetero geneous distribution of the drug as evidenced by enhanced drug concentrations at several localized areas. The spectrum extracted from the locations in which P E G and ibuprofen were both present shows that ibuprofen in this formulation exists in its crystalline form, which is confirmed by comparing the position of the carbonyl band in Figure 4 to the reference spectrum in Figure 2. Further-more, a


208 previous study has shown that the carbonyl band of crystalline ibu-profen absorbs at 1710 cm" , which is in agreement with the carbonyl position shown in Figure 4. (18) The images in Figure 3 show the distribution of P E G and ibuprofen after the flow of water had started.


1

Figure 3. Grey-scale images showing the absorbance of PEG (top row) and ibuprofen (bottom row) change during the dissolution of the tablet prepared by the mechanical method. The dark area indicates a high absorbance, while the light area indicates a low absorbance. The image area is ca. 1140 x 820 pm . 2

P E G dissolves gradually, almost completely disappearing after 58 minutes. As P E G dissolves, a small amount of ibuprofen advances away from the initial position within the tablet for the first six minutes and then starts to accumulate, forming a large cluster of crystals. The movement of the ibuprofen is apparently caused by the swelling of P E G , pushing several smaller drug particles for a small distance. However, as dissolved P E G is quickly removed by the water flow, the


209


movement of the drug ended after a short distance (ca. 300 pm). Evidently, the used water flow was not sufficient to carry away the drug particles.

Figure 4. FTIR spectra extractedfromtablet images prepared by the mechanical (grey) and melt (black) methods.

The images also show that the area where the ibuprofen concentration suddenly increases coincides with the area where P E G disappears completely. This suggests the deposition of ibuprofen particles on the A T R crystal after the removal of P E G by water. This type of dissolution mechanism has been described as "drug-controlled". (2) The solubility of the drug in the polymerrich diffusion layer is low, hence the drug release rate will be controlled by the dissolution of solid drug particles.

Dissolution of the Sample Prepared by the Melt Method. Before the dissolution, the image in Figure 5 at 0 min shows a well-defined and sharp edge of the tablet and a very uniform distribution of the polymer in the measured tablet area. Figure 5 also reveals that ibuprofen is homogeneously distributed within the sample. The black dot on the top right corner and the white dot on the bottom left corner are due to bad pixels of the F P A detector. The infrared spectrum extracted from the measured tablet area shows a shift of the carbonyl band position to 1720 cm" (see Figure 4), indicating that the drug is molecularly dispersed in the polymer matrix. 1



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Figure 5. Grey-scale images showing the absorbance of PEG (top row) and ibuprofen (bottom row) change during the dissolution of the tablet prepared by the melt method. The dark area indicates a high absorbance, while the light area indicates a low absorbance. The image area is ca. 1140 x 820 pm . 2

The images in Figure 5 show that P E G at the edges of the tablet dissolves quickly as the flow of water begins, leading to a less-defined tablet edge. However, the images at the following time intervals reveal two distinct steps in the P E G concentration formed 3 minutes after the water addition. This behavior is different from the observations in previous studies, where P E G formed a smooth variation in the distribution. (7,8) The image of ibuprofen revealed the formation of a line of increased concentration at the edge of the tablet after the beginning of the water flow. This line grew between the images captured at 1 and 3 minutes. The observed increase of the ibuprofen concentration in that area was caused by crystallization of ibuprofen, which was originally molecularly dispersed within the polymer matrix. A similar phenomenon has been observed


211 in a previous study using static water. (7) This result shows that flow of water does not remove the formed layer of a drug barrier. Spectra from three different regions, A , B and C, of the image shown in Figure 5 have been extracted for direct comparison. These spectra are shown in Figure 6. The spectra measured at location B represent the non-dissolved part of the tablet, as indicated by the shoulder at 1060 cm' , a distinct feature of semicrystalline PEG. The position of the carbonyl band at B indicates that ibuprofen is still molecularly dispersed at that point. The disappearance of the shoulder at 1060 cm" at location A together with the appearance of the absorption band due to the bending mode vibration of water at 1640 cm" is a good indication that PEG is being dissolved in this region. However, the position of the carbonyl band of ibuprofen measured in that region remains at 1720 cm' . This behavior is probable caused by the high concentration of P E G (although it is already dissolved), preventing the crystallization of ibuprofen. Further investigation is required to prove this hypothesis and will be explored in future studies. Spectra extracted from region C show the spectrum of crystalline ibuprofen, as indicated by the shift of the carbonyl band to 1710 cm" . However, the spectrum also shows the presence of P E G and water in this area. This observation could be explained by the assumption that the drug barrier is not completely impermeable so both, water and dissolved polymer, can still diffuse through this drug barrier. 1

1

1


1

1

Figure 6. FTIR spectra extractedfromareas indicated in Figure 5.



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As a result of the drug barrier formation, water can only enter the dissolving tablet by diffusion though this barrier, causing the tablet to dissolve at a much slower rate. For the sample prepared by the mechanical method, all solid P E G was dissolved 17 minutes after the beginning of dissolution and all P E G was removed after 58 minutes. However, for the sample prepared by the melt method a small amount of solid P E G remained even after 41 minutes of disso lution, and a high concentration of dissolved P E G remained trapped by the drug barrier after 77 minutes from the start of water flow. The flow of water removed all P E G that had diffused away from the tablet through the drug barrier, causing the first steep decrease in P E G concentration. The second decrease in P E G concentration occurred when P E G transformed from the semi-crystalline to the amorphous form before being dissolved. Nevertheless, imaging data of the dissolution of the tablet prepared by the melt method have shown that dissolved ibuprofen traveled a much farther distance away from the initial tablet edge compared to the distance traveled by particles of ibuprofen in the formulation prepared by the mechanical method. The movement of ibuprofen molecules is evident from the image captured after 3 minutes. Unfortunately, it was not possible to estimate how far the drug traveled since it moved beyond the field of view of the imaging setting employed in this study.

Conclusions Dissolution of PEG/ibuprofen formulations prepared by mechanical mixing and melt methods have been studied by FTIR spectroscopic imaging. In this study, FTIR imaging in macro-ATR mode was used to simultaneously measure the spatial distribution of polymer and drug as a function of time upon contact of the prepared tablet with a flow of water. This approach enabled visualization of the processes occurring in tablets, which allowed comparison of dissolution mechanisms of tablets prepared by two different methods. The imaging data revealed that the formation of a drug layer of crystalline ibuprofen in the melt formulation is enhanced by the presence of water flow compared to the analogous experiment with stagnant water. Nevertheless, this layer did not prevent ibuprofen to be distributed farther away from the initial edge of the tablet compared to the distribution of ibuprofen during the dissolution of the tablet prepared by mechanical mixing. This study demonstrated new appli cations of the macro-ATR imaging approach. It has shown that this approach allowed imaging tablet preparations in situ in order to assess the initial distribution of a drug and its molecular state in the polymer matrix. Further more, macro-ATR imaging of tablets in contact with flowing water was possible, allowing to monitor the distribution of both, drug and polymer, and to compare


213 two tablet preparation methods. A tremendous potential exists in the use of this method for studies of controlled release systems.

Acknowledgements We thank EPSRC (grant GR/S03942/01) for funding.


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Dissolution of Solid Dispersions of Ibuprofen Studied by Fourier

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