Impact of the digital revolution on the future of pharmaceutical formulation science.

The ongoing digital revolution is no longer limited to the application of apps on the smart phone for daily needs but starts to affect also our professional life in formulation science. The software platform F-CAD (Formulation-Computer Aided Design) of CINCAP can be used to develop and test in silico capsule and tablet formulations. Such an approach allows the pharmaceutical industry to adopt the workflow of the automotive and aircraft industry. Thus, the first prototype of the drug delivery vehicle is prepared virtually by mimicking the composition (particle size distribution of the active drug substance and of the excipients within the tablet) and the process such as direct compression to obtain a defined porosity. The software is based on a cellular automaton (CA) process mimicking the dissolution profile of the capsule or tablet formulation. To take account of the type of dissolution equipment and all SOPs (Standard Operation Procedures) such as a single punch press to manufacture the tablet, a calibration of the F-CAD dissolution profile of the virtual tablet is needed. Thus, the virtual tablet becomes a copy of the real tablet. This statement is valid for all tablets manufactured within the same formulation design space. For this reason, it is important to define already for Clinical Phase I the formulation design space and to work only within this formulation design space consisting of the composition and the processes during all the Clinical Phases. Thus, it is not recommended to start with a simple capsule formulation as service dosage form and to change later to a market ready tablet formulation. The availability of F-CAD is a necessary, but not a sufficient condition to implement the workflow of the automotive and aircraft industry for developing and testing drug delivery vehicles. For a successful implementation of the new workflow, a harmonization of the equipment and the processes between the development and manufacturing departments is a must. In this context, the clinical samples for Clinical Phases I and II should be prepared with a mechanical simulator of the high-speed rotary press used for large batches for Clinical Phases III & IV. If not, the problem of working practically and virtually in different formulation design spaces will remain causing worldwide annually billion of $ losses according to the study of Benson and MacCabe. The harmonization of equipment and processes needs a close cooperation between the industrial pharmacist and the pharmaceutical engineer. In addition, Virtual Equipment Simulators (VESs) of small and large scale equipment for training and computer assisted scale-up would be desirable. A lean and intelligent management information and documentation system will improve the connectivity between the different work stations. Thus, in future, it may be possible to rent at low costs F-CAD as an IT (Information Technology) platform based on a cloud computing solution. By the adoption of the workflow of the automotive and aircraft industry significant savings, a reduced time to market, a lower attrition rate, and a much higher quality of the final marketed dosage form can be achieved.

An attempt to calculate in silico disintegration time of tablets containing mefenamic acid, a low water-soluble drug.

Based on a Quality by Design (QbD) approach, it is important to follow International Conference on Harmonization (ICH) guidance Q8 (R2) recommendations to explore the design space. The application of an experimental design is, however, not sufficient because of the fact that it is necessary to take into account the effects of percolation theory. For this purpose, an adequate software needs to be applied, capable of detecting percolation thresholds as a function of the distribution of the functional powder particles. Formulation-computer aided design (F-CAD), originally designed to calculate in silico the drug dissolution profiles of a tablet formulation is, for example, a suitable software for this purpose. The study shows that F-CAD can calculate a good estimate of the disintegration time of a tablet formulation consisting of mefenamic acid. More important, F-CAD is capable of replacing expensive laboratory work by performing in silico experiments for the exploration of the formulation design space according to ICH guidance Q8 (R2). As a consequence, a similar workflow existing as best practice in the automotive and aircraft industry can be adopted by the pharmaceutical industry: The drug delivery vehicle can be first fully designed and tested in silico, which will improve the quality of the marketed formulation and save time and money.

Investigation of compressibility and compactibility parameters of roller compacted Theophylline and its binary mixtures.

Roller compaction is a dry granulation method which results in tablets with inferior tensile strength comparing to direct compaction. The effect of roller compaction on compressibility and compactibility of tablets prepared from Theophylline anhydrate powder, Theophylline anhydrate fine powder and Theophylline monohydrate was investigated by measuring tensile strength of tablets as well as calculating compressibility and compactibility parameters by Leuenberger equation. The tablets under the same conditions were prepared by direct compaction and roller compaction. The binary mixtures of Theophylline anhydrate powder, Theophylline anhydrate fine powder, Theophylline monohydrate and microcrystalline cellulose were prepared in order to determine the optimal ratio of active material and excipients which delivers a sufficient mechanical strength of tablets. Tensile strength of MCC tablets and compactibility parameters calculated by Leuenberger equation after roller compaction was significantly decreased, while THAP, THAFP and THMO tablets showed only a minor reduction in compactibility and compressibility. Adding MCC to a mixture with Theophylline showed that the right choice and ratio of excipients can enable a sufficient mechanical strength of the tablets after roller compaction.

Development of push-pull osmotic tablets using chitosan-poly(acrylic acid) interpolymer complex as an osmopolymer.

The objectives of this study were to prepare push-pull osmotic tablets (PPOT) of felodipine using an interpolymer complex of chitosan (CS) and poly(acrylic acid) (PAA) as an osmopolymer, and to study the mechanisms of drug release from these tablets. The interpolymer complexes were prepared with different weight ratios of CS to PAA. Preparation of PPOT involved the fabrication of bilayered tablets with the drug layer, containing felodipine, polyethylene oxide, and the polymeric expansion layer, containing the CS-PAA complex. The effects of polymer ratios, type of plasticizers, and compression forces on release characteristics were investigated. It was found that drug release from PPOT exhibited zero-order kinetics and could be prolonged up to 12 or 24 h depending on the plasticizer used. PPOT using dibutyl sebacate showed a longer lag time and slower drug release than that using polyethylene glycol 400. In the case of polyethylene glycol 400, an increase in the CS proportion resulted in an increase in the drug release rate. The compression force had no effect on drug release from PPOT. Drug release was controlled by two consecutive mechanisms: an osmotic pump effect resulting in the extrusion of the drug layer from the tablet and subsequent erosion and dissolution of the extruded drug layer in the dissolution medium. The mathematical model (zero-order) related to extrusion and erosion rates for describing the mechanism of drug release showed a good correlation between predicted and observed values.

Roller compaction of different pseudopolymorphic forms of theophylline: Effect on compressibility and tablet properties.

The effect of roller compaction on disintegration time, dissolution rate and compressibility of tablets prepared from theophylline anhydrate powder, theophylline anhydrate fine powder and theophylline monohydrate was studied. In addition, the influence of adding microcrystalline cellulose, a commonly used excipient, in mixtures with these materials was investigated. Theophylline anhydrate powder was used as a model drug to investigate the influence of different compaction pressures on the tablet properties. Tablets with same porosity were prepared by direct compaction and by roller compaction/re-compaction. Compressibility was characterized by Heckel and modified Heckel equations. Due to the property of polymorphic materials to change their form during milling and compression, X-ray diffraction analysis of theophylline anhydrate powder, theophylline anhydrate fine powder and theophylline monohydrate powders and granules was carried out. After roller compaction the disintegration time and the dissolution rate of the tablets were significantly improved. Compressibility of theophylline anhydrate powder and theophylline anhydrate fine powder was decreased, while theophylline monohydrate showed higher compressibility after roller compaction. Microcrystalline cellulose affected compressibility of theophylline anhydrate powder, theophylline anhydrate fine powder and theophylline monohydrate whereby the binary mixtures showed higher compressibility than the individual materials. X-ray diffraction analyses confirmed that there were no polymorphic/pseudopolymorphic changes after roller compaction.

Investigation of intrinsic dissolution behavior of different carbamazepine samples.

The aim of the present study was to investigate the effect of the variability of commercially available carbamazepine (CBZ) samples on the intrinsic dissolution behavior in order to recommend a strategy to maintain product quality by monitoring the variability of critical parameters of the bulk drug. Extensive physical characterization of nine anhydrous CBZ samples from three different sources and their respective dihydrates showed that the commercial anhydrous CBZ samples exhibited the same polymorphic form, but different morphology and particle size distribution which led to a variation in the kinetics of conversion from anhydrous to the dihydrate CBZ and therefore to variation in the kinetics of solubility. Disc intrinsic dissolution rate (DIDR) tests showed different intrinsic dissolution behavior of the samples, whereby the transition points of anhydrous to dihydrate conversion varied between 15 and 25 min. On the other hand, converting the anhydrous CBZ's to dihydrate eliminated the variation in intrinsic dissolution behavior. Tablets of the different CBZs and Ludipress were prepared by direct compression. The amount of CBZ dissolved after 15 min showed the same rank order as the rank order of the transition points determined by intrinsic dissolution test. Therefore, the intrinsic dissolution test with specific acceptance criteria can be a valuable and simple tool for monitoring, respectively reducing the variability of the CBZ bulk material.

Terahertz pulsed imaging and near infrared imaging to monitor the coating process of pharmaceutical tablets.

Terahertz pulsed imaging (TPI) and near infrared (NIR) imaging were used to non-destructively monitor the coating process of film-coated tablets. Samples that were taken from a pan coater at different time points were analyzed by both methods. TPI provided coating thickness maps over the whole surface of the tablets, determining the thickness of the coating at each point of the sample surface in mum, this way also giving information about the coating uniformity. The growth of the coating during the coating process was shown. NIR imaging did not provide direct thickness values, but by different absorbance values, inter- and intra-tablet differences were shown. Thus, coating thickness information was also obtained in a way that different tablets could be compared. The growth of the coating layer during the process was shown as well. Both methods provided comparable results; and they were able to detect small defects in the coating. With TPI, the whole tablet surface could be scanned; with NIR imaging information about the tablet ends at the center-band was not obtained due to the strong curvature. NIR imaging proved to be better at thinner coating layers and had a higher spatial resolution whereas TPI had the clear advantage that it provided direct thickness values.

Influence of loading volume of mefenamic acid on granules and tablet characteristics using a compaction simulator.

Mefenamic acid (MA), a poorly water-soluble drug, was used as a model substance to investigate granules and tablet characteristics to be optimized for the loading volume of MA (0-74.1% v/v) in the formulation including lactose monohydrate/maize starch (7/3) as excipients. The compactibility of granules increased with loading volume of MA. This was related to the brittle behavior of MA during compression and the increase of intragranular pore volume of granules. The minimum disintegration time (266 +/- 8.3 s) was found in the tablet that was composed of 55.1% v/v MA and 13.6% v/v maize starch. The determination of the critical concentration of disintegrant (% v/v) required for a minimum disintegration time may be useful for solid dosage form design.

Rational estimation of the optimum amount of non-fibrous disintegrant applying percolation theory for binary fast disintegrating formulation.

The purpose of this study was to propose a method of determining the exact value of disintegrant ratio in a binary drug-disintegrant compacted mixture for a minimum disintegration time in the case of spherical particles. Disintegration is a limiting factor in dissolution process of compact for low water soluble active ingredients. As disintegration time is shortest at a certain ratio of disintegrant, a calculation of this value is important for solid dosage from design to enhance disintegration and dissolution process. According to percolation theory, a minimum disintegration time corresponds to the formation of a continuous water-conducting cluster through the entire tablet. The critical volumetric ratio at which the cluster is formed is named percolation threshold and has the value of 0.16 for random close packed (RCP) sphere systems. RCP systems where chosen as the best model for compacts consisting of spherical particles. Two cases for water diffusion through the tablet were identified, according to geometrical considerations between disintegrant and drug particles. These cases determine if disintegrant particles can have a contact between each other within the compact and thus if porosity and disintegrant volume are included in the continuous cluster. An equation for both cases is presented in the form of piecewise function to determine the minimal disintegrant volumetric ratio for a binary drug/disintegrant compact in order to achieve a minimum disintegration time. Disintegration tests were performed with tablets at different ratios of modified corn starch mixed with caffeine or paracetamol powders. Estimated and experimental optimal ratio were compared showing coefficient R(2) = 0.96.

Influence of loading volume of mefenamic acid on granules and tablet characteristics using a compaction simulator.

Mefenamic acid (MA), a poorly water-soluble drug, was used as a model substance to investigate granules and tablet characteristics to be optimized for the loading volume of MA (0-74.1% v/v) in the formulation including lactose monohydrate/maize starch (7/3) as excipients. The compactibility of granules increased with loading volume of MA. This was related to the brittle behavior of MA during compression and the increase of intragranular pore volume of granules. The minimum disintegration time (266+/-8.3 s) was found in the tablet that was composed of 55.1% v/v MA and 13.6% v/v maize starch. The determination of the critical concentration of disintegrant (% v/v) required for a minimum disintegration time is suggested to be useful for solid dosage form design.

Preference of dairy cows for ryegrass, white clover and red clover, and its effects on nutrient supply and milk quality.

Two experiments were conducted with 30 dairy cows each, to study the preference for fresh (Experiment 1) and ensiled (Experiment 2) ryegrass, white and red clover. Both experiments consisted of three choice diets with white or red clover or both, offered with ryegrass, and two diets with ryegrass mixed with white or red clover (40% clover). Cows consumed diets with 37.7% fresh white and 45.9% red clover, and no preference was observed when the cows were offered all three forages. By contrast, cows preferred white and red clover silage (73.0 and 69.2%, respectively) over ryegrass silage (of lower nutritive quality). When offered three forages, cows preferred white (59.8%) over red clover (17.5%) and ryegrass (22.7%). Choice diets resulted in diets similar (fresh forages) or higher in nutrient content and digestibility (silages). Treatments did not affect feed intake and performance. Choices compared to mixed diets with red clover silage were preferable regarding the fatty acid composition of the milk fat. Obviously, only large differences in nutrient and energy concentration facilitate preferences for clovers over ryegrass, which could, depending on clover type, be beneficial in terms of the milk's fatty acid composition.

Percolation theory and the role of maize starch as a disintegrant for a low water-soluble drug.

The objective of the present work is to investigate the presence or absence of a critical concentration of maize starch according to the percolation theory for a truly ternary system with respect to a minimum disintegration time. The results of this study show that the application of percolation theory is not limited to the study of binary systems. In this work it is shown how it can be used to analyze the behavior of binary and ternary systems for caffeine and mefenamic acid formulations containing a starch-based disintegrant. The percolation threshold p(c) can be described by the volumetric ratio of the disintegrant to the drug substance being equal to p(c) = 0.2 (v/v) in in which both components have similar average particle sizes. In addition, the behavior of the disintegration time in the neighborhood of the percolation threshold can be mathematically modeled with the basic equation of the percolation theory yielding a critical exponent q = 0.28 +/- 0.06.

The characterization of aprotic polar liquids and percolation phenomena in DMSO/water mixtures.

In the previous papers of our research group it was shown, that the Clausius-Mossotti-Debye equation for the quasi-static dielectric constant (epsilonr) can be extended to liquids if the parameter Ei/E is introduced. Thus, it is possible to characterize polar liquids with the easily accessible parameter Ei/E. This property is also reflected by the fact that the parameter Ei/E can be directly related to the empirical ET(30) and the normalized ETN parameter to describe the polarity of liquids proposed by Reichardt (Chem. Rev. 94, 2319-2358) Ei corresponds to the local mean field due to close molecule-molecule interactions after the application of an external electric field E. In a recent work of our research group it was also demonstrated that the modified Clausius-Mossotti-Debye equation and the study of the relaxation time can be related to percolation phenomena in binary solvent mixtures leading to a valuable insight of the structure of polar liquids and to a better understanding of binary systems. In the present paper it is demonstrated that percolation phenomena for binary DMSO/water mixtures, become visible due to changes of parameters describing the dielectric spectrums. The interpretation of the percolation effects leads to the following conclusion: DMSO/water mixtures seem to have in the whole range of miscibility the same microscopic structure like water with a coordination number z approximately between 4 and 6 which could be the reason for the high permeability of DMSO through biological membranes.

In vivo comparison of various liposome formulations for cosmetic application.

The interaction of liposome formulations, prepared with phospholipids of different origins (egg and soya), with skin were compared in terms of their effects on skin water content, skin barrier function, and skin elasticity. Short-term effect of four different liposome formulations and two references during 3.5 h was investigated non-occlusively on the volar side of the forearm of 10 volunteers, ranging in age from 24 to 32 years. Liposomes composed of different phospholipids showed differing effects on skin humidity. The maximal effect was achieved within 30 min and constant values were reached after 1.5 h for all formulations, however values remained significantly higher than without treatment (p<0.05) during the whole application time. The best results were obtained with liposome formulations prepared from egg phospholipids, which exhibited a 1.5-fold increase in skin water content (p<0.05), whereas liposome formulations prepared from soya phospholipids showed no advantage compared to the references. Skin barrier function showed greatest influence within 30 min after application and remained constant after 1.5 h for all formulations. Within the liposome formulations, egg phospholipids showed the highest transepidermal water loss values during the first 30 min, representing the strongest interactions with the skin barrier function, whereas for the other liposome formulations lower transepidermal water loss values were measured. Skin elasticity and tiring effect of the skin was not influenced by any of the formulations, due to the young skin tested. Long-term effect of two different liposome formulations mixed with base cream DAC in two different concentrations during 14 days was investigated non-occlusively on the volar side of the forearm of 10 volunteers, ranging in age from 20 to 25 years. Skin water content was measured daily and the results showed that skin humidity was increased significantly (p<0.05) for the formulation containing 20% egg phospholipids during 6 days. Liposome formulations prepared with egg phospholipids showed significantly higher (p<0.01) hydration effects during 3.5 h of application on human skin compared with liposome formulations prepared with soya phospholipids.

Preparation of dry powder inhalation with lactose carrier particles surface-coated using a Wurster fluidized bed.

An attempt was made to produce carrier particles for dry powder inhalation with lactose carrier particles surface-coated using a Wurster fluidized bed. The lactose carrier particles were coated with lactose aqueous solution containing hydroxypropyl methyl cellulose (HPMC) as a binder using a Wurster coating apparatus. Drug/carrier powder mixtures were prepared consisting of micronized salbutamol sulfate and lactose carriers under various particle surface conditions. These powder mixtures were aerosolized by a Jethaler((R)), and the in vitro deposition properties of salbutamol sulfate were evaluated by a twin impinger. The in vitro inhalation properties of the powder mixture prepared using the coated lactose carrier differed significantly compared with those of the powder mixture prepared using the uncoated lactose carrier, indicating improvements in in vitro inhalation properties of sulbutamol sulfate. In vitro inhalation properties increased with the surface coating time. This surface coating system would thus be valuable for increasing the in vitro inhalation properties of dry powder inhalation with lactose carrier particles.

Towards a better understanding of the parameter Ei/E in the characterization of polar liquids.

In the two previous papers [Stengele, A., Rey, St., Leuenberger, H., 2001. A novel approach to the characterization of polar liquids. Part 1: pure liquids. Int. J. Pharm. 225, 123-134; Stengele, A., Rey, St., Leuenberger, H., 2002. A novel approach to the characterization of polar liquids. Part 2: binary mixtures. Int. J. Pharm. 241, 231-240] it was shown, that the Clausius-Mossotti-Debye equation for the quasi-static dielectric constant (epsilon) can be extended to liquids if the parameter Ei/E is introduced. Ei corresponds to the local mean field due to close molecule-molecule interactions after the application of an external electric field E. In the present paper, it is demonstrated that the value of Ei/E at room temperature can be (1) related to the density of hydroxy groups and the density of the square of the dipole moment per molar volume for polar liquids and (2) also to the total (deltat) and partial solubility parameter, for polar (deltap) and hydrogen bond forming molecules (deltah).

Detection of percolation phenomena in binary polar liquids by broadband dielectric spectroscopy.

In the previous papers [Stengele, A., Rey, St., Leuenberger, H., 2001. A novel approach to the characterization of polar liquids. Part 1: pure liquids. Int. J. Pharm. 225, 123-134; Stengele, A., Rey, St., Leuenberger, H., 2002. A novel approach to the characterization of polar liquids. Part 2: binary mixtures. Int. J. Pharm. 241, 231-240], it was shown that the Clausius-Mossotti-Debye equation for the quasi-static dielectric constant (epsilon) can be extended to liquids if the parameter Ei/E is introduced. Ei corresponds to the local mean field due to close molecule-molecule interactions after the application of an external electric field E. In the present paper it is demonstrated that the Ei/E parameter and the relaxation behavior of the dipole moment of the polar molecule in binary mixtures of water, respectively, methanol or benzylalcohol with 1,4-dioxane can be used for the detection of percolation phenomena. As 1,4-dioxane has no intrinsic dipole moment but can form hydrogen bonds and is completely miscible with water, respectively, methanol or benzylalcohol, percolation phenomena can be related to the relaxation behavior of the dipole moment of the polar co-solvent. The relaxation behavior of the binary mixtures can be modeled by applying the Debye equation, and the Cole-Davidson distribution function. Superpositions such as the Debye equation and the Cole-Davidson distribution function or a sum (Sigmai) of Debye equations are also considered.

Search for technological reasons to develop a capsule or a tablet formulation with respect to wettability and dissolution.

Proquazone, a poorly wettable compound, was used as a model drug in the search for reasons to develop a capsule or tablet formulation. The capsules were filled with proquazone as active ingredient, with lactose monohydrate (200 mesh) as filler and with magnesium stearate as lubricant. The tablet was made out of a granulate as internal phase which consisted of proquazone as active ingredient, lactose as filler, corn starch as disintegrant and PVP as a binding agent. The external phase consisted of magnesium stearate and corn starch. The concentration of proquazone in the capsule and in the tablet formulation was varied. The capsule formulations showed a significantly slower dissolution of the drug substance than the tablet formulations especially for a high-drug load. Independently of the drug load, only the tablet formulation showed a high-dissolution rate. Thus, concerning drug load, only the tablet formulations showed to be robust. It became clear that proquazone needs to be formulated as a granulate or a tablet to achieve a fast dissolution rate. Thus, a poorly wettable drug, especially when it is found in high concentrations, can have direct impact on the decision to develop a tablet or a capsule formulation.

Power consumption measurement and temperature recording during granulation.

This study was performed to elucidate the influences of process and formulation design using power consumption and temperature measurements during granulation. Power consumption was recorded "in process" using a previously introduced computer program for optimal end-point detection at an early stage. The temperature increase (DeltaT) during granulation was recorded using a temperature sensor. The temperature increase in the wet powder bed expresses the friction forces at interparticle contacts occurring during granulation. The maxima of temperature profile occurred at 130% saturation, whereas the maxima of power consumption were determined at 100% saturation. The ratio of temperature and power consumption (TPR factor) is introduced as a signature of formulation design. TPR factor was found to be dependent on particle size, particle surface, water absorption capacity and solubility of the excipient and model drug, respectively. However, TPR factor was found to be independent of process design, such as the filling level of the mixer. Understanding and controlling the granulation process is a key factor in robust dosage form design. The "in process" control fits ideally the prerequisites of a drug quality system for the 21st century and FDA's Process Analytical Technology (PAT) initiative. The results of previous and present works of our research group will be used in a following step to develop an artificial neural network for granulation "in process" control.