Design Space and Control Strategy for the Manufacturing of Wet Media Milled Drug Nanocrystal Suspensions by Adopting Mechanistic Process Modeling.

Wet media milling is a fully industrialized technology for the manufacturing of drug nanocrystal suspensions. This work describes the development of an advanced control strategy and an associated design space for a manufacturing process at a commercial scale. Full-scale experiments and mechanistic process modeling have been used to establish a physically reasonable control strategy of factors relevant to the quality attributes of the nanocrystal suspension. The design space has been developed based on a mature mechanistic process model of the wet media milling procedure. It presents the process-product attribute relationship between a multidimensional range of measured process parameters and a range of the product-quality attribute mean particle sizes. The control strategy allows for simple, robust, and sound scientific process control as well as the operational flexibility of the suspension batch size. This is an industrial case study of control strategy and design-space definition with the crucial contribution of mechanistic process modeling for an intended commercial manufacturing process.

Numerical modeling of the dissolution of drug nanocrystals and its application to industrial product development.

The apparent solubility of drug nanocrystals in equilibrium was experimentally determined for a drug-stabilizer system with different particle size distributions. True supersaturation was identified for ultrafine drug nanocrystals with an almost 2-fold increase compared to the thermodynamic solubility of related coarse drug crystals, highlighting their enabling potential to enhance bioavailability. The experimental results were applied to investigate in silico the associated dissolution behavior in a closed system by numerical modeling according to the Ostwald-Freundlich and Noyes-Whitney / Nernst-Brunner equations. Calculated results were found to be in agreement with the experimental results only when the entire particle size distribution of drug nanocrystals was considered. In silico dissolution, studies were conducted to simulate the complex interplay between drug nanocrystals, dissolution conditions and resulting temporal progression during dissolution up to the equilibrium state. Calculations were performed for selected in vivo and in vitro scenarios considering different drug nanocrystal particle size distributions, drug amount, dissolution media and volume. The achieved results demonstrated the importance of ultrafine drug nanocrystals for potential bioavailability improvement and the functional applicability of the modeling approach to investigate their dissolution behavior for configurable formulation variables in product development in terms of in vivo and in vitro relevant conditions.

Influence of the drug deformation behaviour on the predictability of compressibility and compactibility of binary mixtures.

Various studies investigate the predictability of the compressibility and compactibility of tablet formulations based on the behaviour of the pure materials. However, these studies are limited to a few materials so far probably because of the complexity of the powder compaction process. One approach preventing the excessive increase in complexity is the extension of the investigations from pure materials to binary powder mixtures. The focus of this study is on the predictability of the compressibility and compactibility of binary mixtures consisting of an active pharmaceutical ingredient (API) and the excipient microcrystalline cellulose. Three APIs with markedly different deformation behaviour were used. The API concentration and type are systematically varied. For all three material combinations it is found that the in-die compressibility of the binary mixtures can be precisely predicted based on the characteristic compression parameters of the raw materials using the extended in-die compression function in combination with a volume-based linear mixing rule. Since the tablet porosity (out-of-die) also follows a linear mixing rule, the predictability can be further extended using the method of Katz et al. In contrast, the influence of the API concentration on compactibility or rather on tablet tensile strength is non-linear and strongly dependent on the deformation behaviour of the API, making the predictability more difficult. Neither the approach of Reynolds et al. nor this of Kuentz and Leuenberger are able to predict the compactibility when clear deviations from a linear mixing rule appear.

Evaluation of the Formulation Parameter-Dependent Redispersibility of API Nanoparticles from Fluid Bed Granules.

The production of nanosuspensions of poorly soluble active pharmaceutical ingredients (API) is a popular technique to counteract challenges regarding bioavailability of such active substances. A subsequent drying of the nanosuspensions is advantageous to improve the long-term stability and the further processing into solid oral dosage forms. However, associated drying operations are critical, especially with regard to nanoparticle growth, loss in redispersibility and associated compromised bioavailability. This work extends a previous study regarding the applicability of an API (itraconazole) nanosuspension as a granulation liquid in a fluidized bed process with focus on the influence of applied formulation parameters on the structure of obtained nanoparticle-loaded granules and their nanoparticle redispersibility. Generally, a higher dissolution rate of the carrier material (glass beads, lactose, mannitol or sucrose) and a higher content of a matrix former/hydrophilic polymer (PVP/VA or HPMC) in the granulation liquid resulted in the formation of coarser and more porous granules with improved nanoparticle redispersibility. HPMC was found to have advantages as a polymer compared with PVP/VA. In general, a better redispersibility of the nanoparticles from the granules could be associated with better dispersion of the API nanoparticles at the surface of the granules as deduced from the thickness of nanoparticle-loaded layers around the granules. The layer thickness on granules was assessed by means of confocal Raman microscopy. Finally, the dispersion of the nanoparticles in the granule layers was exemplarily described by calculation of theoretical mean nanoparticle distances in the granule layers and was correlated with data obtained from redispersibility studies.

Prediction of the impact of lubrication on tablet compactibility.

The tableting of most pharmaceutical formulations requires the addition of lubricants to reduce ejection forces, prevent tooling damage and tablet defects. The internal addition of lubricants is known to reduce tablet tensile strength, especially of mainly plastically deforming materials. To date, available models show only limited quantitative predictive accuracy for the influence of lubricant concentration on the mechanical strength of tablets. This study aims to fill this gap and present a model based on the Ryshkewitch-Duckworth equation that can estimate the compactibility profiles of lubricated formulations. Binary mixtures of different diluents (microcrystalline cellulose and lactose) were prepared with common lubricants (magnesium stearate and sodium stearyl fumarate) and subsequently tableted. The resulting compactibility profiles were fitted using the Ryshkewitch-Duckworth equation and the derived fit parameters (kb and σ0) were correlated with the lubricant concentration. Subsequently, an empirical model was established which requires a minimum of experimental data and is able to predict the tensile strength of lubricated diluent tablets. Consequently, the developed empirical model is an interesting and valuable addition to the existing multi-component compacting models available and offers the opportunity to accelerate experimentation in the development of new tablet formulations.

Tablet Disintegration and Dispersion under In Vivo-like Hydrodynamic Conditions.

Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due to the frequent occurrence of high hydrodynamic forces, among other reasons. In this study, 3D tomographic laser-induced fluorescence imaging (3D Tomo-LIF) is applied to analyse tablet disintegration and dispersion. Disintegration time (DT) and time-resolved particle size distribution in close proximity to the tablet are determined in a continuously operated flow channel, adjustable to very low fluid velocities. A case study on tablets of different porosity, which are composed of pharmaceutical polymers labelled with a fluorescent dye, a filler, and disintegrants, is presented to demonstrate the functionality and precision of the novel method. DT results from 3D Tomo-LIF are compared with results from the SDT, confirming the analytical limitations of the pharmacopoeial disintegration test. Results from the 3D Tomo-LIF method proved a strong impact of fluid velocity on disintegration and dispersion. Generally, shorter DTs were determined when cross-linked sodium carboxymethly cellulose (NaCMCXL) was used as disintegrant compared to polyvinyl polypyrrolidone (PVPP). Tablets containing Kollidon VA64 were found to disintegrate by surface erosion. The novel method provides an in-depth understanding of the functional behaviour of the tablet material, composition and structural properties under in vivo-like hydrodynamic forces regarding disintegration and the temporal progress of dispersion. We consider the 3D Tomo-LIF in vitro method to be of improved biorelevance in terms of hydrodynamic conditions in the human stomach.

Tablet formulation development focusing on the functional behaviour of water uptake and swelling.

The functional behaviour of tablets is strongly influenced by their manufacturing process and the choice of excipients. Water uptake and swelling are prerequisites for tablet disintegration, dispersion and hence active pharmaceutical ingredient (API) dissolution. High proportions of polymeric excipients in tablets, which are typically used as API carriers in amorphous solid dispersions (ASDs), may be challenging due to the formation of a gelling polymer network (GPN). In this study, systematic investigations into the formulation development of tablets containing polymeric and other excipients are performed by water uptake and swelling analysis. The impact of tablet composition and porosity as well as pH of the test medium are investigated. The pH affects the analysis results for Eudragit L100-55 and Eudragit EPO. HPMC and Kollidon VA64 inhibit water uptake and swelling of tablets due to the formation of a GPN. High tablet porosity, coarse particle size of the polymer and the addition of fillers and disintegrants can reduce the negative impact of a GPN on tablet performance. The application of lubricants slows down the analysed processes. Water uptake and swelling data are fitted to an empirical model obtaining four characteristic parameters to facilitate the simple quantitative assessment of varying tablet formulations and structural properties.

How can single particle compression and nanoindentation contribute to the understanding of pharmaceutical powder compression?

The deformation behaviour of a powder and, thus, of the individual particles is a crucial parameter in powder compaction and affects powder compressibility and compactibility. The classical approach for the characterization of the deformation behaviour is the performance of powder compression experiments combined with the application of mathematical models, such as the Heckel-Model, for the derivation of characteristic compression parameters. However, the correlation of these parameters with the deformation behaviour is physically often not well understood. Single particle compression and nanoindentation enables the in-depth investigation of the deformation behaviour of particulate materials. In this study, single particle compression experiments were performed for the characterization of the deformation behaviour of common pharmaceutical excipients and active pharmaceutical ingredients (APIs) with various, irregular particle morphologies of industrial relevance and the findings are compared with the results from powder compression. The technique was found useful for the characterization and clarification of the qualitative deformation behaviour. However, the derivation of a quantitative functional relationship between single particle deformation behavior and powder compression is limited. Nanoindentation was performed as complementary technique for the characterization of the micromechanical behavior of the APIs. A linear relationship between median indentation hardness and material densification strength as characteristic parameter derived by in-die powder compression analysis is found.

The influence of particle size on the application of compression and compaction models for tableting.

The physical characteristics of raw materials determine powder compression and compaction performance as relevant in pharmaceutical processes. For instance, the influence of initial particle size on powder compression and the resulting strength of specimen are highly complex and are still not sufficiently understood. Existing studies are often limited to materials with well-defined deformation behaviour, such as purely brittle or ductile. However, the deformation behaviour of active pharmaceutical ingredients (APIs) is often more complex. In this study, the influence of initial particle size on powder compressibility and compactibility is systematically characterized by consideration of in-die compressibility, specific energies, quick elastic recovery, tablet porosity and, tensile strength for the binder microcrystalline cellulose and three APIs. The decrease of particle size leads to an increase of the resistance against compression by trend and probably to a different contribution of the acting deformation mechanisms. The compactibility is increased with decreasing particle size because of the increasing number of bonds in a cross-sectional area of the tablet, as found by the application of the model of Rumpf. Furthermore, it is found that the model of Rumpf combined with the JKR model provides a meaningful property function to estimate tablet tensile strength.

An improved method for the simultaneous determination of water uptake and swelling of tablets.

Water uptake and swelling of tablets are processes occurring during active pharmaceutical ingredient (API) release. Thereby, disintegration is promoted and the enhanced exposure of API surface area to the release medium facilitates API dissolution. An experimental set-up for the simultaneous and time-resolved determination of water uptake and swelling of tablets has been developed. Water uptake was determined with a balance and swelling was determined with a camera. To validate the gravimetrical analysis, real-time water uptake measurements with inert test specimens were performed. The standard deviation of these measurements was considered to depict precision. A complementary gravimetrical analysis was employed to determine accuracy. For both, precision and accuracy, a maximum deviation of 6% was found. An algorithm for the symmetry-based 3D volume reconstruction was applied to obtain volumes of the tablets from 2D images. X-ray micro computed tomography was used to validate the accuracy and the determined volumes were in good accordance within 6% deviation. A case study with binary formulations of a filler and disintegrants confirmed reproducibility and demonstrated the ability of the method to discriminate formulation characteristics, such as disintegrant type, composition and porosity for water uptake and swelling with the necessary temporal resolution.

Spray drying of API nanosuspensions: Importance of drying temperature, type and content of matrix former and particle size for successful formulation and process development.

Active pharmaceutical ingredient (API) nanosuspensions from naproxen (Nap) and itraconazole (Itra) stabilized with Kollidon®VA64 (KVA) and sodium dodecyl sulfate (SDS) were produced in two different size classes each by wet media milling. These API nanosuspensions were spray dried with lactose, trehalose and sucrose as matrix formers in different proportions and at different drying temperatures (Toutlet). Toutlet as well as the API content significantly influenced the redispersibility of the API nanoparticles. It could be shown that these two parameters are related to each other, with an increasing API content leading to a decreasing maximum applicable Toutlet (Tcritical). Drying above Tcritical always led to an alteration of the size characteristics of the API nanoparticles and thus to a non-redispersible product with respect to the defined quality criteria. For each proportion of API to matrix former, a Tcritical could be found. Tcritical showed a linear relation to the API content. The linear regression of this relation was defined as process boundary. The y-intercept of the process boundary correlated well with the glass transition temperature (Tg) of the pure matrix former used for spray drying. The two APIs under investigation led to virtually identical behaviour if other parameters were kept constant. The particle size of the initial nanosuspension had an important influence. Nanosuspensions with comparatively small particle sizes led to a significantly stronger decrease of the process boundaries compared to the use of larger particle sizes. The maximum API content that leads to a redispersible product is thus decisively determined by Toulet of the spray dryer, Tg as well as the proportion of the matrix former and by the particle size of the API nanoparticles used.

Influence of Formulation Parameters on Redispersibility of Naproxen Nanoparticles from Granules Produced in a Fluidized Bed Process.

The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient's convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the influence of several formulation parameters (i.e., type of carrier material, type and amount of additional polymeric drying excipient in the nanosuspension) on the redispersibility of naproxen nanoparticle-loaded granules produced in a fluidized bed process was investigated. The dissolution rate of the carrier material (i.e., sucrose, mannitol, or lactose) was identified as a relevant material property, with higher dissolution rates (sucrose > mannitol > lactose) resulting in better redispersibility of the products. Additionally, the redispersibility of the product granules was observed to improve with increasing amounts of polymeric drying excipient in the nanosuspension. The redispersibility was observed to qualitatively correlate with the degree of nanoparticle embedding on the surface of the corresponding granules. This embedding was assumed to be either caused by a partial dissolution and subsequent resolidification of the carrier surface dependent on the dissolution rate of the carrier material or by resolidification of the dissolved polymeric drying excipient upon drying. As the correlation between the redispersibility and the morphology of the corresponding granules was observed for all investigated formulation parameters, it may be assumed that the redispersibility of the nanoparticles is determined by their distance in the dried state.

A Mathematical Approach to Consider Solid Compressibility in the Compression of Pharmaceutical Powders.

In-die compression analysis is an effective method for the characterization of powder compressibility. However, physically unreasonable apparent solid fractions above one or apparent in-die porosities below zero are often calculated for higher compression stresses. One important reason for this is the neglect of solid compressibility and hence the assumption of a constant solid density. In this work, the solid compressibility of four pharmaceutical powders with different deformation behaviour is characterized using mercury porosimetry. The derived bulk moduli are applied for the calculation of in-die porosities. The change of in-die porosity due to the consideration of solid compressibility is for instance up to 4% for microcrystalline cellulose at a compression stress of 400 MPa and thus cannot be neglected for the calculation of in-die porosities. However, solid compressibility and further uncertainties from, for example the measured solid density and from the displacement sensors, are difficult or only partially accessible. Therefore, a mathematic term for the calculation of physically reasonable in-die porosities is introduced. This term can be used for the extension of common mathematical models, such as the models of Heckel and of Cooper & Eaton. Additionally, an extended in-die compression function is introduced to precisely describe the entire range of in-die porosity curves and to enable the successful differentiation and quantification of the compression behaviour of the investigated pharmaceutical powders.

Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane.

PURPOSE: The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (µFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature. METHOD: Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of µFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane. In addition to the flux evaluations, changes in solid state as a function of time were investigated to gain further insight into the flux changes observed over time for the solid dispersion formulations. RESULTS: Initial flux values from Sporanox®, the nanosuspension and the micronized ITZ showed ratios of 52/4/1 with a decreasing flux from nanosuspension and both solid dispersions after 2.5-3 h. Although the initial flux from the Soluplus® formulation was 2.2 times lower than the one observed for Sporanox®, the decrease in flux observed was milder and became ~ 2 times higher than Sporanox® after approximately 2.5 h. The total amounts of ITZ in the receiver compartment after 240 min showed the same rank order as the rodent AUCs of these formulations reported in literature. CONCLUSIONS: It was demonstrated that in vitro flux measurements using lipophilic artificial membranes could correctly reproduce the rank order of PK results for ITZ formulations. The drop in flux over time for solid dispersions could be backed by experimental indications of crystallization.

Alternative Manufacturing Concepts for Solid Oral Dosage Forms From Drug Nanosuspensions Using Fluid Dispensing and Forced Drying Technology.

Flexible manufacturing technologies for solid oral dosage forms with a continuous adjustability of the manufactured dose strength are of interest for applications in personalized medicine. This study explored the feasibility of using microvalve technology for the manufacturing of different solid oral dosage form concepts. Hard gelatin capsules filled with excipients, placebo tablets, and polymer films, placed in hard gelatin capsules after drying, were considered as substrates. For each concept, a basic understanding of relevant formulation parameters and their impact on dissolution behavior has been established. Suitable matrix formers, present either on the substrate or directly in the drug nanosuspension, proved to be essential to prevent nanoparticle agglomeration of the drug nanoparticles and to ensure a fast dissolution behavior. Furthermore, convection and radiation drying methods were investigated for the fast drying of drug nanosuspensions dispensed onto polymer films, which were then placed in hard gelatin capsules. Changes in morphology and in drug and matrix former distribution were observed for increasing drying intensity. However, even fast drying times below 1 min could be realized, while maintaining the nanoparticulate drug structure and a good dissolution behavior.

Impact of Formulation Properties and Process Parameters on the Dispensing and Depositioning of Drug Nanosuspensions Using Micro-Valve Technology.

Flexible manufacturing processes with continuously adjustable dose strengths are considered particularly innovative and interesting for applications in personalized medicine, continuous manufacturing, or early drug development. A piezo-actuated micro-valve has been investigated for the dispensing and depositioning of drug nanosuspensions onto substrates to facilitate the manufacturing of solid oral dosage forms. The investigated micro-valve has been characterized regarding dispensing behavior, mass flow, accuracy, and robustness. The amount of dispensed drug compound during 1 dispensing event could be continuously adjusted from a few micrograms to several milligrams with high accuracy. Fluid properties, dispensing parameters of the micro-valve, and the resulting steady state mass flow could be correlated adequately for low-viscous drug nanosuspensions. High-speed imaging was used to investigate the dispensing behavior of the micro-valve regarding the evolution of the dispensed drug nanosuspension after ejection from the nozzle and the behavior during impact on flat and dry solid substrates. The experimentally determined breakup length of the dispensed liquid jet could be correlated with a semiempirical equation. From image sequences of the jet impact, We-Re phase diagrams could be established, providing a profound understanding and systematic guidance for the controlled depositioning of the entire dispensed drug nanosuspension onto the substrate.

Generation of wear during the production of drug nanosuspensions by wet media milling.

Wet media milling is an established technique for the commercialized top-down production of nanoparticulate drug suspensions. These drug nanosuspensions can be transferred into the related drug products, like capsules, tablets and injectables. The generation of wear during stirred media milling of a drug compound was investigated for grinding media made from yttrium stabilized zirconia. Drug compound and drug nanosuspension were characterized initially by their mechanical and rheological properties. The generation of wear from grinding media has been investigated simultaneously with the reduction of drug particle size by evaluating several grinding media supplier and diameter as well as process parameters stirrer tip speed and specific energy input. Grinding media quality and process parameters were identified with strong impact on the amount of generated wear and on drug particle size distribution. Wear from grinding media characterized by elemental zirconium and yttrium could be significantly minimized by operating with the favored grinding media quality and with optimal stirrer tip speed and specific energy input. Wear debris, respectively wear particles from grinding media, were identified with respect to morphology and particle size. Finally, the overall contamination by raw materials and by wear during processing characterized by elemental iron, silicium, yttrium and zirconium as well as the mean size of contamination particles are presented for selected drug nanosuspensions.