Jouko Yliruusi

Prediction of physicochemical properties based on neural network modelling

The literature describing neural network modelling to predict physicochemical properties of organic compounds from the molecular structure is reviewed from the perspective of pharmaceutical research. The standard three-layer, feed-forward neural network is the technique most frequently used, although the use of other techniques is increasing. Various approaches to describe the molecular structure have been successfully used, including molecular fragments, topological indices, and descriptors calculated by semi-empirical quantum chemical methods. Some physicochemical properties, such as octanol-water partition coefficient, water solubility, boiling point and vapour pressure, have been modelled by several research groups over the years using different approaches and structurally diverse large training sets. The prediction accuracy of most models seems to be rather close to the performance of the experimental measurements, when the accuracy is assessed with a test set from the working database. Results with independent test sets have been less satisfactory. Implications of this problem are discussed.

Controlled release injectable liposomal gel of ibuprofen for epidural analgesia.

The epidural administration is used commonly in the treatment of pain. Nonsteroidal anti-inflammatory drugs, especially ibuprofen, would have potential in epidural use. Like many epidurally useful drugs it, however, has a short duration of action, which is a limiting factor. To improve epidural pain treatment, a long-acting, single-dose gel injection is being developed. In the present study, the possibility of using liposomal systems to control the release and dural permeation of ibuprofen was investigated in vitro. Liposomal solutions of ibuprofen.Na (20 mg/ml) were prepared by high-pressure homogenization from egg phosphatidylcholine. The liposomal gel consisted of poloxamer 407 and the liposomal solution. No signs in the 1H-NMR spectroscopy of line broadenings or chemical shifts were observed. The liposomal formulations were reproducible and stable. Ibuprofen release in phosphate buffer, pH 7.4, at 37 degrees C from the liposomal solution and the liposomal gel were prolonged significantly compared with their respective solution and gel controls. The liposomal gel controlled ibuprofen release and dural permeation in vitro and showed a permeation pattern favourable for maintaining constant drug levels. The liposomal poloxamer gel represents a new formulation approach to increase the local epidural availability of ibuprofen. It appeared to be a promising injectable controlled-release drug delivery system.

Controlled Release of Lidocaine from Injectable Gels and Efficacy in Rat Sciatic Nerve Block

AbstractPurpose. Methods of delaying the action of local anesthetics are important, since short duration of action limits their use in the treatment of postoperative and chronic pain. The present study evaluated the use of low-viscosity gels in prolonging the release of lidocaine. Methods. Release of lidocaine from 2% lidocaine-HC1 containing methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodiumcarboxymethyl cellulose (CMC), and poloxamer 407 (PO) gels was studied in phosphate buffer, pH 7.4, at 37°C. Commercial metylcellulose gel (MCcom) served as control. The in vivo efficacy of the respective gel formulations were evaluated in rats. The gel was injected into the vicinity of the sciatic nerve and nociception and motor function were tested. Results. The cumulative amount of lidocaine released during 8 hr was slowest from the PO gel, followed by the CMC, HPMC and MC gels. The antinociceptive effect was not prevented by the motor block and lasted longest with the PO gel. Good linear and rank order correlation was obtained between in vitro and in vivoresults. The microscopic examination of the tissue samples revealed only mild or no irritation of the skeletal muscle tissue by the PO, HPMC, and CMC gels. Conclusions. Based on these results poloxamer gel proved to be the most promising carrier for lidocaine.

On-line monitoring of moisture content in an instrumented fluidized bed granulator with a multi-channel NIR moisture sensor

The applicability of a near-infrared reflectance spectroscopic method was tested. The set-up used was constructed for the determination of water during different unit operations performed in a fluidized bed granulator. The granulation of three different formulations and the drying of one pellet formulation were investigated. The pellets were prepared by the continuous extrusion spheronisation technique. It proved possible to measure the moisture content of granules with a standard error of performance of 0.2%. The reference method used was based on the measurement of loss on drying (infrared dryer, wet basis). The applicability of the near-infrared method in pharmaceutical formulation and process development work was investigated using different liquid flow rates and drying end points. Combining the continuous measurement of moisture content and the product temperature measurement creates a novel tool for observing both the granule spraying and the drying phase. Different moisture profiles of the granules were clearly distinguished as well as the different drying end points.

Extrusion-spheronization of pH-sensitive polymeric matrix pellets for possible colonic drug delivery.

The aim of this study was to investigate extrusion-spheronization pelletization for preparing pH-sensitive matrix pellets for colon-specific drug delivery. The effects of three independent variables (amounts of Eudragit S, citric acid and spheronizing time) on pellet size, shape (roundness and aspect ratio), and drug release were studied with central composite design. The pellets contained ibuprofen as a model drug, citric acid as a pH-adjusting agent, Eudragit S as a pH-sensitive binder and microcrystalline cellulose (MCC). The pellets were prepared with Nica extrusion-spheronizing equipment and subsequently enteric-coated using an air-suspension technique. Eudragit S as a pH-sensitive matrix former in pellets increased the pellet size and influenced pellet roundness. In small amounts Eudragit S increased pellet roundness but in larger amounts pellet roundness was reduced. Citric acid promoted the pelletization process resulting in a narrower area distribution. The pH-sensitive matrix pellet failed to delay the drug release. The combination of citric acid and enteric coating, however, delayed the drug release for 15 min in a pH 7.4 phosphate buffer.

Better understanding of dissolution behaviour of amorphous drugs by in situ solid-state analysis using Raman spectroscopy

Amorphous drugs have a higher kinetic solubility and dissolution rate than their crystalline counterparts. However, this advantage is lost if the amorphous form converts to the stable crystalline form during the dissolution as the dissolution rate will gradually change to that of the crystalline form. The purpose of this study was to use in situ Raman spectroscopy in combination with either partial least squares discriminant analysis (PLS-DA) or partial least squares (PLS) regression analysis to monitor as well as quantify the solid-phase transitions that take place during the dissolution of two amorphous drugs, indomethacin (IMC) and carbamazepine (CBZ). The dissolution rate was higher from amorphous IMC compared to the crystalline alpha- and gamma-forms. However, the dissolution rate started to slow down during the experiment. In situ Raman analysis verified that at that time point the sample started to crystallize to the alpha-form. Amorphous CBZ instantly started to crystallize upon contact with the dissolution medium. The transition from the amorphous form to CBZ dihydrate appears to go through the anhydrate form I. Based on the PLS analysis the amount of form I formed in the sample during the dissolution affected the dissolution rate. Raman spectroscopy combined with PLS-DA was also more sensitive to the solid-state changes than X-ray powder diffraction (XRPD) and was able to detect changes in the solid-state that could not be detected with XRPD.

In-line moisture measurement during granulation with a four-wavelength near infrared sensor: an evaluation of particle size and binder effects.

Factors affecting in-line near infrared (NIR) moisture measurement with a four-wavelength sensor were evaluated (choice of binder used in granulation liquid and the increase in particle size). An entire NIR spectrum is not necessary for the measurement of water, and often the use of only a few NIR wavelengths around the water band enables reliable and high-speed detection of moisture. Glass ballotini and microcrystalline cellulose (MCC) were used as model test materials. The binders studied were poly[1-(2-oxo-1-pyrrolidinyl)ethylene] (PVP) and gelatin. Full off-line NIR spectra of test materials at different levels of binder solutions were measured. The major spectral features for both the binders were bands around 1700 nm (first overtones CH related stretches) and 2200 nm (combination bands). Gelatin also had an NH band around 1500 nm (first overtones of NH stretches) and combination bands at about 2050 nm. Particle size effects were observed as an increase in spectra baseline. All these factors should be considered when choosing NIR wavelengths used for detection of water with a fixed wavelength set-up. A robust calibration model enables the development of in-process control of wet granulation processes.

Hydrate Formation During Wet Granulation Studied by Spectroscopic Methods and Multivariate Analysis

AbstractPurpose. The aim was to follow hydrate formation of two structurally related drugs, theophylline and caffeine, during wet granulation using fast and nondestructive spectroscopic methods. Methods. Anhydrous theophylline and caffeine were granulated with purified water. Charge-coupled device (CCD) Raman spectroscopy was compared with near-infrared spectroscopy (NIR) in following hydrate formation of drugs during wet granulation (off-line). To perform an at-line process analysis, the effect of water addition was monitored by NIR spectroscopy and principal components analysis (PCA). The changes in the crystal arrangements were verified by using X-ray powder diffraction (XRPD). Results. Hydrate formation of theophylline and caffeine could be followed by CCD Raman spectroscopy. The NIR and Raman spectroscopic results were consistent with each other. NIR revealed the state of water, and Raman spectroscopy gave information related to the drug molecule itself. The XRPD confirmed the spectroscopic results. PCA with three principal components explained 99.9of the spectral variation in the second derivative NIR spectra. Conclusions. Both CCD Raman and NIR spectroscopic methods can be applied to monitoring of hydrate formation processes. However, NIR is more suitable for monitoring solid-water interactions.

Controlled release and dura mater permeability of lidocaine and ibuprofen from injectable poloxamer-based gels

Epidural administration of drugs is becoming more common in the treatment of severe forms of pain. To improve present therapies, a long-acting single-dose gel injection would be beneficial. The present study investigated the use of three different polymers as additives in injectable poloxamer gel in controlling the drug release. The release of lidocaine.HCl and ibuprofen.NA from 25% poloxamer (PO) gel and poloxamer gel with hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC), or dextran (DE) was studied in vitro. Cellulose additives significantly prolonged ibuprofen release, whereas additives were found to have a slight release-increasing effect on lidocaine as compared with the PO gel. The structural differences of the gels, more than the macroviscosity, seem to regulate the release of drugs. The drug permeation-prolonging effect of the respective gels, along with the control solutions, was evaluated in vitro using porcine dura mater membrane. The compact gel depot acted as the rate-limiting step, and significantly prolonged the dural permeation of both drugs in comparison with control solutions. The difference in the drug release and permeation-reducing effects of the gels demonstrated the possibility for interactions between dural membrane and the gel. The findings are promising for further experimental in vivo animal testing of these injectable poloxamer-based gels.

Novel Identification of Pseudopolymorphic Changes of Theophylline During Wet Granulation Using Near Infrared Spectroscopy

The purpose of this study was to demonstrate the efficiency of near infrared (NIR) spectroscopy in studying the pseudopolymorphic changes and the state of water during the wet granulation process. Anhydrous theophylline was granulated in a planetary mixer using water as granulation liquid. NIR spectra and differential scanning calorimetric (DSC) and wide-angle X-ray scattering (WAXS) patterns of theophylline granules, anhydrous theophylline, and theophylline monohydrate were measured. At a low level of granulation liquid (0.3 mol of water per mole of anhydrous theophylline), water absorption maxima in the NIR region occurred first at around 1475 and 1970 nm. These absorption maxima were identical to those of theophylline monohydrate. At higher levels of granulation liquid (1.3-2.7 mol of water per mole of anhydrous theophylline), the increasing absorption maxima occurred at 1410 and 1905 nm due to OH vibrations of free water molecules. X-ray diffraction patterns confirmed the transformation of anhydrous theophylline to theophylline monohydrate during wet granulation. NIR spectroscopy was able to detect different states of water molecules during the wet granulation process faster and in a more flexible manner than conventional methods.