Multivariate analysis for optimization and validation of the industrial tablet-manufacturing process.

OBJECTIVE: This study aimed initially to optimize the industrial tablet-manufacturing process using multivariate analysis, and then to validate the model obtained. The study also provides a comprehensive review of the influence of different factors on relevant biopharmaceutical parameters. SIGNIFICANCE: This is the first time multivariate analysis has been applied to such a broad set of industrial data to investigate the influence of starting materials and the tablet-manufacturing processes on drug dissolution. METHODS: Partial least squares regression was retrospectively applied to the data obtained from 2 years production, to study the influence of 90 factors on dissolution of tablets that contained two active pharmaceutical ingredients. The model established was verified using the worst-case approach and process validation. RESULTS: Croscarmellose sodium had the most significant influence on drug dissolution, with the next significant factors as sodium chloride and sodium glycolate content, settling volume, particle size, suspension pH, loss on drying, and maximum temperature during drying. Loss on drying of microcrystalline cellulose and specific surface area of magnesium stearate were also essential factors. Among the process parameters, auger speed during roller compaction, compression speed, and force feeder speed during tablet compression had significant impacts on the tablet dissolution rate. The multivariate model created satisfied the process validation. CONCLUSIONS: This multivariate analysis is a useful tool to predict and optimize critical material attributes and process parameters. The variability of the materials can be successfully compensated for using various process parameters, to ensure consistent approved drug quality, to thus provide better patient care.

Step-wise approach to developing a scale-independent design space for functional tablet coating process.

The objective of this study is to present a practical example of a scale-independent design space development using a step-wise approach. A detailed description of the development process with a systematic outline of the main steps is provided. Design space is developed for film coating of tablets with moisture protective polyvinyl alcohol (PVA) based coating. The impact of scale-independent coating process parameters on the properties of film-coated tablets (FCT), i.e. water activity and film coating protection ability, and consequently on product long-term stability is explored. The main finding is that with model simplifications, a step-wise approach and rational development of scale-independent design space for the coating process, it is possible to efficiently predict, control, and optimize the long-term stability of a moisture sensitive product. However, the PVA moisture protective coating itself is recognized as having conflicting effects on product stability.

Correction to: Impact of Buffer, Protein Concentration and Sucrose Addition on the Aggregation and Particle Formation during Freezing and Thawing.

The statement in the caption to Fig. 1 "Data taken from reference (38)." (Kolhe P, Holding E, Lary A, Chico S, Singh SK. Large-scale freezing of biologics: understanding protein and solute concentration changes in a Cryovessel-part 2. Biopharm International. 2010;23(7):40-9) is erroneous.

The environmental monitoring in hospital pharmacy cleanroom and microbiota catalogue preparation.

Knowing the normal cleanroom microbiota is the basis for ensuring microbiological quality; assess changes and the introduction of new sampling methods. During our study, we prepared a catalogue of cleanroom microorganisms located in four different cleanrooms in University Clinical Centre Ljubljana Pharmacy. Catalogue is prepared as a basis for assessing the suitability of the new rapid microbiological method and subsequent correlation of the results of both methods. The results of our study showed that 78% of isolated bacteria are Gram-positive. However, in more than 70% isolated bacteria were the part of the normal human microbiota, 10-15% of the microorganisms originated from the air, mainly spore-forming bacteria of the genus Bacillus and fungi, and 5-10% of the Gram-negative microorganisms that originated from the water and represent the potential endotoxins (pyrogens).

Impact of Buffer, Protein Concentration and Sucrose Addition on the Aggregation and Particle Formation during Freezing and Thawing.

PURPOSE: This study addresses the effect of freezing and thawing on a therapeutic monoclonal antibody (mAb) solution and the corresponding buffer formulation. Particle formation, crystallization behaviour, morphology changes and cryo-concentration effects were studied after varying the freezing and thawing rates, buffer formulation and protein concentration. The impact of undergoing multiple freeze/thaw (FT)-cycles at controlled and uncontrolled temperature rates on mAb solutions was investigated in terms of particle formation. METHODS: Physicochemical characteristics were analysed by Differential Scanning Calorimetry whereas morphology changes are visualized by cryomicroscopy measurements. Micro Flow Imaging, Archimedes and Dynamic Light Scattering were used to investigate particle formation. RESULTS: Data retrieved in the present study emphasizes the damage caused by multiple FT-cyles and the need for sucrose as a cryoprotectant preventing cold-crystallization specifically at high protein concentrations. Low protein concentrations cause an increase of micron particle formation. Low freezing rates lead to a decreased particle number with increased particle diameter. CONCLUSION: The overall goal of this research is to gain a better understanding of the freezing and thawing behaviour of mAb solutions with the ultimate aim to optimize this process step by reducing the unwanted particle formation, which also includes protein aggregates.

Scientific, statistical, practical, and regulatory considerations in design space development.

The quality by design (QbD) paradigm guides the pharmaceutical industry towards improved understanding of products and processes, and at the same time facilitates a high degree of manufacturing and regulatory flexibility throughout the establishment of the design space. This review article presents scientific, statistical and regulatory considerations in design space development. All key development milestones, starting with planning, selection of factors, experimental execution, data analysis, model development and assessment, verification, and validation, and ending with design space submission, are presented and discussed. The focus is especially on frequently ignored topics, like management of factors and CQAs that will not be included in experimental design, evaluation of risk of failure on design space edges, or modeling scale-up strategy. Moreover, development of a design space that is independent of manufacturing scale is proposed as the preferred approach.

Granular Matter Transport in Vertical Pipes: The Influence of Pipe Outlet Conditions on Gravity-driven Granular Flow.

Gravity transport of granular materials in vertical pipes is one of the most fundamental steps in bulk powder handling and processing. Presented study investigates powder flow characteristics in vertical pipes with open and closed outlets and condition of free powder fall. Powder flow of pharmaceutical grade powders was observed in transparent, vertical pipe model. Description of flow structures was performed. Powder volume flow rate, acceleration, and dilatation were quantified and correlated with powder properties. The results show that in pipes with a closed outlet the escaping air slows down the powder flow, resulting in a much slower flow than in pipes with an open outlet. A dense granular flow was detected in an open outlet condition, whereas in a closed outlet condition two concurrent flow regimes were observed: a slow moving, dense powder bed, and a fast dilute powder flow. Differences in flow regimes may promote segregation, with important implications to industrial processes.

Nanomechanical properties of selected single pharmaceutical crystals as a predictor of their bulk behaviour.

PURPOSE: The main goal of this research was to assess the mechanical properties of APIs' polymorphic forms at the single-crystal level (piroxicam, famotidine, nifedipine, olanzapine) in order to predict their bulk deformational attributes, which are critical for some pharmaceutical technology processes. METHODS: The mechanical properties of oriented single crystals were determined using instrumented nanoindentation (continuous stiffness measurement). All polymorphic forms investigated were previously identified using a combination of calorimetric and spectroscopic techniques. RESULTS: Mechanical properties such as Young's modulus and indentation hardness were consistent with the molecular packing of the polymorphic forms investigated with respect to crystal orientation. For mechanically interlocked structures, characteristic of most polymorphic forms, response of single crystals to indentation was isotropic. The material's bulk elastic properties can be successfully predicted by measuring Young's modulus of single crystals because a good linear correlation with a bulk parameter such as the tablets' elastic relaxation index was determined. CONCLUSIONS: The results confirm the idea that the intrinsic mechanical properties of pharmaceutical crystals (Young's modulus) largely control and anticipate their deformational behavior during tablet compression. Young's modulus and indentation hardness represent a very valuable and effective tool in preformulation studies for describing materials' mechanical attributes, which are important for technological processes in which materials are exposed to deformation.

Determination of Solubility Parameters of Ibuprofen and Ibuprofen Lysinate.

In recent years there has been a growing interest in formulating solid dispersions, which purposes mainly include solubility enhancement, sustained drug release and taste masking. The most notable problem by these dispersions is drug-carrier (in)solubility. Here we focus on solubility parameters as a tool for predicting the solubility of a drug in certain carriers. Solubility parameters were determined in two different ways: solely by using calculation methods, and by experimental approaches. Six different calculation methods were applied in order to calculate the solubility parameters of the drug ibuprofen and several excipients. However, we were not able to do so in the case of ibuprofen lysinate, as calculation models for salts are still not defined. Therefore, the extended Hansen's approach and inverse gas chromatography (IGC) were used for evaluating of solubility parameters for ibuprofen lysinate. The obtained values of the total solubility parameter did not differ much between the two methods: by the extended Hansen's approach it was δt = 31.15 MPa(0.5) and with IGC it was δt = 35.17 MPa(0.5). However, the values of partial solubility parameters, i.e., δd, δp and δh, did differ from each other, what might be due to the complex behaviour of a salt in the presence of various solvents.

Melt granulation in fluidized bed: a comparative study of spray-on versus in situ procedure.

OBJECTIVE: The aim of this study was to investigate the influence of process parameters, binder content and binder addition method on characteristics of the granules obtained by melt granulation (MG) in fluidized bed. METHODS: Spray-on experiments were performed according to 2(3) full factorial design. The effect of binder content, molten binder feed rate, and spray air pressure on granule size and size distribution, granule shape, flowability and drug release rate was investigated. In the in situ experiments, the influence of binder particle size and binder content was evaluated. Solid-state characterization was performed by means of differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. RESULTS: Size of the granules obtained by spray-on procedure was significantly influenced by binder content and spray air pressure, while the width of particle size distribution was mainly affected by binder feed rate. Spray air pressure showed the most significant influence on granule shape. It was shown that smooth and spherical particles with good flow properties may be obtained by both procedures, spray-on and in situ MG. The results obtained indicated the influence of agglomeration mechanism on granule sphericity, with higher degree of granule sphericity observed when immersion and layering was the dominant mechanism. Paracetamol release from granulates was very rapid, but after compression of the granules into tablets, drug release was considerably slower. Solid-state analysis confirmed that the physical form of the granulate components remained unaffected after the MG process. CONCLUSION: The results presented indicate that MG in fluidized bed could be a good alternative to conventional granulation techniques.

Fluid-bed coater modifications and study of their influence on the coating process of pellets.

OBJECTIVE: In this study, different modifications of bottom spray fluid-bed coater with draft tube inserted were characterized and evaluated. MATERIALS AND METHODS: After coating the neutral pellets with polymeric solution comprising coloring agent pellet batches were characterized for coating variation, yield and degree of agglomeration. RESULTS: Funnel-shaped distribution plate was found to improve process yield and decrease the degree of agglomeration at selected values of process parameters, whereas coating uniformity was worse in all cases when compared to conventional Wurster chamber. Results of the coating chamber with the swirl airflow generator indicate more uniform deposition of the coating material and in some cases an improved process yield and decreased formation of agglomerates when compared to conventional Wurster chamber. In series of experiments using Wurster chamber, having tangentially oriented air intake slots, which enabled introduction of air above the distribution plate, coating layer was more uniformly deposited on the pellet cores and formation of agglomerates was lower compared to the results obtained in a conventional Wurster coating chamber. CONCLUSION: Modifications of Wurster coating process by introducing swirling air motion within the draft tube or by introduction of air above the distribution plate have at selected values of process parameters resulted in reduced per-particle coating variation, degree of agglomeration and improved process yield.

Comparative study of the uniformity of coating thickness of pellets coated with a conventional Wurster chamber and a swirl generator-equipped Wurster chamber.

This study evaluated the performance of two bottom-spray coaters and the effect of pellet-size variability on coating uniformity. A conventional Wurster chamber was used for the first group of trials, and a Wurster chamber with a novel swirl-flow generator design was used for the second. The results confirmed that when using a conventional Wurster coating chamber, pellets with a smaller diameter receive significantly less coating material compared to those with larger diameters. The swirl generator-equipped Wurster chamber achieved close to uniform coating thickness regardless of pellet size. The ratio (M(S)) of the mass of dye deposited in the coating layer to pellet surface area indicates that coating was much more evenly distributed using the swirl-flow coater. Coating thickness was also analyzed using SEM micrographs and the results were in close agreement with the M(S) factor values. Inter-particle coating mass variation was also lower in case of swirl-flow coater. The results of this study show that a swirl-flow coater is suitable for coating particles of variable size. They also showed an improvement in coating process yield when using the swirl-flow coater.

Development of a multiple-unit tablet containing enteric-coated pellets.

Film coating of pellets is a common way to design modified-release systems. The aim of this study was to produce a multiple-unit tablet compressed from enteric-coated pellets. The dosage form should comply with Pharmacopoeial demands, especially regarding dissolution, but preferably also all other parameters, including sufficient hardness for packaging procedures. Various approaches, such as using different cushioning excipients, using different enteric coating polymers, changing the tablet shape, and application of an additional protective coating, were employed to develop the dosage form. The final formulation released 9.0 ± 1.8% of the drug in an acidic medium and was compliant regarding uniformity of mass, content, and friability, and had a hardness of 59 N. An optimal coating was obtained by mixing two acrylic polymers: relatively brittle Eudragit® L30 D-55 with more flexible Eudragit® FS 30 D. A mixture of Avicel® PH 101 as filler and Kollidon(®) VA 64 as dry binder was found to be optimal as a cushioning excipient. It was found that tablet shape and an additional protective pellet coating of Kollidon(®) VA 64 were the key elements for this development. A biconvex tablet shape was found to approximately halve the release in an acidic medium compared to a round flat-faced tablet.

Evaluation of ATP bioluminescence for monitoring surface hygiene in a hospital pharmacy cleanroom.

The usefulness of the ATP bioluminescence method for monitoring surface hygiene was evaluated in a hospital pharmacy cleanroom. The sensitivity of the method was found to be appropriate for assessing the efficiency of cleaning and disinfection. ATP bioluminescence was superior to the traditional microbiological culture-based method for detecting unclean surfaces (p < .05).

Utilization of Ethylcellulose Microparticles with Rupatadine Fumarate in Designing Orodispersible Minitablets with Taste Masking Effect.

Minitablets in orodispersible form constitute a flexible drug delivery tool for paediatric and geriatric population as they eliminate the risk of chocking and do not require drinking water in the application. Due to their direct contact with taste buds, taste sensation is an important factor. Preparing microparticles with taste masking polymers utilizing spray drying is an efficient technique for reducing the bitterness of drugs. Ethylcellulose is a hydrophobic polymer widely used as a taste masking material. Rupatadine fumarate, one of the newest antihistamines, features an intensive bitter taste, hence in designing orodispersible formulations, achieving an acceptable taste is a crucial issue. The main objective of this work was to formulate orodispersible minitablets containing taste masked ethylcellulose-based microparticles with rupatadine fumarate and evaluation of their quality, especially in terms of taste masking efficacy. The accessed data indicated that all obtained minitablets were characterized by beneficial pharmaceutical properties. Three independent methods: in vivo with healthy volunteers, in vitro drug dissolution, and "electronic tongue" confirmed that all designed formulations provided satisfactory taste masking rate and that formulation F15 (prepared with Pearlitol® Flash and Surelease® microparticles with rupatadine fumarate) was characterized by the lowest bitterness score.

Polymorphism in Sulfanilamide: 14N Nuclear Quadrupole Resonance Study.

To demonstrate the selectivity of 14N nuclear quadrupole resonance (14N NQR) spectroscopy in chemistry and pharmacy, a study of sulfanilamide polymorphism was undertaken. We studied 3 known polymorphs of sulfanilamide by 14N NQR. We found at room temperature 2 sets of 3 14N NQR transition frequencies, corresponding to 2 different nitrogen sites in the crystal structure for each of 3 polymorphs. We measured the temperature dependence of all quadrupole frequencies ν+, ν-. In each set, only 1 of the 3 14N NQR frequencies is enough to characterize the polymorph. Spin-lattice relaxation time (T1) measurement is supplemental information. We also measured the transition temperature between polymorphs and estimated the ratio of polymorphs after thermal treatment of sample.

Physico-chemical characterisation of different clindamycin phosphate samples.

For the majority of the pharmaceutical dosage forms, the substances that are used maintain solid state under the standard storage conditions, i.e. powders. The interactions of pharmaceutical powders (active ingredient(s) and excipients) with liquids and vapors (particularly aqueous solutions and their vapors) occur almost always during the production process. From the physical point of view, the interactions among individual components may differ from the expected because chemically identical substances obtained from different producers vary very much. These differences influence either the production process and/or the pharmaceutical form properties. In order to overcome these problems it is necessary to establish a control over the physico-chemical properties of the used materials. The aim of this work was to determine physico-chemical properties of three powder clindamycin phosphate samples (labeled as sample S(1), S(2) and S(3)) acquired through different suppliers. All the analysis were made for the purpose of establishing possible differences among the tested samples that showed variable physical stability in the solution: recrystallization of the S(3) sample in the aqueous solution has been established during storage under standard conditions. On the basis of the obtained data it was possible to recognize the differences among the tested clindamycin phosphate samples and to explain the anomalous behavior of one sample. The surface free energy components for the investigated clindamycin phosphate samples were determined using Wu and Good- van Oss method. The investigated clindamycin phosphate samples exhibit certain differences in surface free energy values as well as in surface morphology and thermal behavior. Comparison of alpha + and alpha - values leads to the conclusion that all three clindamycin phosphate samples perform as monopolar, more electron acceptors, i.e. Lewis acids. However, an important difference exists between samples S(1) and S(2) on one and S(3) on the other side. Sample S(3) exhibits stronger acidic behavior, what could be connected with its recrystallization during the storage. The samples S(1), S(2) and S(3) have different melting points e.g. "onset" temperatures. When the melting points move towards 200 (o ) C, the width of the "onset" temperature peak is especially important. In the case of wider peak, the potential for recrystallization seems to be higher. According to the stated, the sample S1 would be the "sample of choice" for the formulation of the stable pharmaceutical dosage form and has not shown any recrystallization tendencies during the storage period.

EMA and EFSA Joint Scientific Opinion on measures to reduce the need to use antimicrobial agents in animal husbandry in the European Union, and the resulting impacts on food safety (RONAFA).

EFSA and EMA have jointly reviewed measures taken in the EU to reduce the need for and use of antimicrobials in food-producing animals, and the resultant impacts on antimicrobial resistance (AMR). Reduction strategies have been implemented successfully in some Member States. Such strategies include national reduction targets, benchmarking of antimicrobial use, controls on prescribing and restrictions on use of specific critically important antimicrobials, together with improvements to animal husbandry and disease prevention and control measures. Due to the multiplicity of factors contributing to AMR, the impact of any single measure is difficult to quantify, although there is evidence of an association between reduction in antimicrobial use and reduced AMR. To minimise antimicrobial use, a multifaceted integrated approach should be implemented, adapted to local circumstances. Recommended options (non-prioritised) include: development of national strategies; harmonised systems for monitoring antimicrobial use and AMR development; establishing national targets for antimicrobial use reduction; use of on-farm health plans; increasing the responsibility of veterinarians for antimicrobial prescribing; training, education and raising public awareness; increasing the availability of rapid and reliable diagnostics; improving husbandry and management procedures for disease prevention and control; rethinking livestock production systems to reduce inherent disease risk. A limited number of studies provide robust evidence of alternatives to antimicrobials that positively influence health parameters. Possible alternatives include probiotics and prebiotics, competitive exclusion, bacteriophages, immunomodulators, organic acids and teat sealants. Development of a legislative framework that permits the use of specific products as alternatives should be considered. Further research to evaluate the potential of alternative farming systems on reducing AMR is also recommended. Animals suffering from bacterial infections should only be treated with antimicrobials based on veterinary diagnosis and prescription. Options should be reviewed to phase out most preventive use of antimicrobials and to reduce and refine metaphylaxis by applying recognised alternative measures.

Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets.

During the past few years, the studies of bi- and multi-layered tablets increased due to the consumption of several different drugs per day by a patient and requests for appropriate patient compliance. The demographic shift toward older population increases the use of combination therapy as polypharmacy. Hydrochlorothiazide (HCTZ), as a model drug, is most commonly used in the treatment of hypertension, congestive heart failure and as a diuretic. The aim of the present study is to investigate the effect of the local environment on dissolution and stability behaviour of HCTZ in fixed multilayered tablet combinations, which are commonly used in polypharmacy. For this purposes, three different systems were introduced: (i) two conventional tablets (HCTZ and pH modifying placebo), (ii) 2-layer tablets (HCTZ, pH modifying placebo) and (iii) 3-layer tablets (HCTZ, barrier and pH modifying placebo). Disintegration of tablets, dissolution of HCTZ from tablets and HCTZ related substances were monitored for all systems. Results showed that there was a significant difference between dissolution profiles of the conventional two-tablet system (HCTZ tablet and pH modifying tablet) and the 2-layer and 3-layer tablets, which include the pH modifying layer. In the case of the conventional two-tablets system, 85 % of HCTZ was dissolved in less than 15 minutes. The dissolution profiles of HCTZ from 2-layered and 3-layered tablets showed a decrease in the dissolution rate. In addition, during the stability studies, it has been confirmed that the typical degradation product of HCTZ is formed, impurity B (4-amino-6-chloro-1,3-benzenedisulfonamide), which implies formation of formaldehyde as hydrolytic impurity not reported in the Ph. Eur. (16). Both impurities are particularly raised in 2-layered tablets with alkaline and neutral placebo layers. Stability of HCTZ was improved in the case of the 3-layer tablet, where the intermediate separation layer of glycerol monostearate was present. It is presumed that the HCTZ dissolution rate was decreased due to formation of non-soluble substances as a result of HCTZ degradation in the presence of alkaline layer.

In silico modeling of in situ fluidized bed melt granulation.

Fluidized bed melt granulation has recently been recognized as a promising technique with numerous advantages over conventional granulation techniques. The aim of this study was to evaluate the possibility of using response surface methodology and artificial neural networks for optimizing in situ fluidized bed melt granulation and to compare them with regard to modeling ability and predictability. The experiments were organized in line with the Box-Behnken design. The influence of binder content, binder particle size, and granulation time on granule properties was evaluated. In addition to the response surface analysis, a multilayer perceptron neural network was applied for data modeling. It was found that in situ fluidized bed melt granulation can be used for production of spherical granules with good flowability. Binder particle size had the most pronounced influence on granule size and shape, suggesting the importance of this parameter in achieving desired granule properties. It was found that binder content can be a critical factor for the width of granule size distribution and yield when immersion and layering is the dominant agglomeration mechanism. The results obtained indicate that both in silico techniques can be useful tools in defining the design space and optimization of in situ fluidized bed melt granulation.