Tableting properties of microcrystalline cellulose obtained from wheat straw measured with a single punch bench top tablet press.

The objective of this work was to study the relation between the manufacturing conditions of microcrystalline cellulose (MCC), its physicochemical properties and its tableting behavior. Two different preparation procedures were used to produce MCC from wheat straw, utilizing an acid hydrolysis method, either using only sulfuric acid or combination of sulfuric and hydrochloric acid. The tableting behavior of obtained MCC samples and mixtures of MCC with ibuprofen was studied using a dynamic powder compaction analyzer. It was observed that some of the obtained MCC samples showed better flowing properties than commercially available Vivapur® PH101 and also very high values of tensile strength, solid fraction and elastic recovery. This can be linked with its good compaction behavior, but on the other hand it can cause problems with the disintegration of the tablets. In mixtures with ibuprofen, MCC samples showed lower values of tensile strength, while on the other hand elastic recovery did not seem to be much affected, still exhibiting very high values. According to the obtained results, it can be concluded that MCC obtained from the agricultural waste could have satisfactory properties for tablet preparation by the direct compression method. Further studies are needed to optimize process conditions in order to achieve better physicochemical characteristics, especially in terms of elastic recovery.

Development of ternary solid dispersions with hydrophilic polymer and surface adsorbent for improving dissolution rate of carbamazepine.

In this study solid dispersions of carbamazepine in the hydrophilic Kollidon® VA64 polymer, adsorbed onto Neusilin® UFL2 adsorption carrier have been employed to improve carbamazepine dissolution rate. In order to evaluate effects of changing in the proportions of all solid dispersion components on carbamazepine dissolution rate, D-optimal mixture experimental design was used in the formulation development. From all prepared solid dispersion formulations, significantly faster carbamazepine dissolution was observed compared to pure drug. Ternary solid dispersions containing carbamazepine, Kollidon® VA64 and Neusilin® UFL2 showed superior dissolution performances over binary ones, containing only carbamazepine and Neusilin® UFL2. Proportion of Kollidon® VA64 showed the most profound effect on the amount of carbamazepine dissolved after 10 and 30 min, whereby these parameters increase upon increasing in Kollidon® VA64 concentrations up to the middle values in the studied range of Kollidon® VA64 concentrations. Physicochemical characterization of the selected samples using differential scanning calorimetry, FT-IR spectroscopy, powder X-ray diffraction and polarizing light microscopy showed polymorphic transition of carbamazepine from more thermodynamically stable monoclinic form (form III) to less thermodynamically stable triclinic form (form I) in the case of ternary, but not of binary solid dispersion formulations. This polymorphic transition can be one of the factors responsible for improving of carbamazepine dissolution rate from studied solid dispersions. Ternary solid dispersions prepared with Kollidon® VA64 hydrophilic polymer and Neusilin® UFL2 adsorption carrier resulted in significantly improvement of carbamazepine dissolution rate, but formation of metastable polymorphic form of carbamazepine requires particular care to be taken in ensuring product long term stability.

Combined application of mixture experimental design and artificial neural networks in the solid dispersion development.

This study for the first time demonstrates combined application of mixture experimental design and artificial neural networks (ANNs) in the solid dispersions (SDs) development. Ternary carbamazepine-Soluplus®-poloxamer 188 SDs were prepared by solvent casting method to improve carbamazepine dissolution rate. The influence of the composition of prepared SDs on carbamazepine dissolution rate was evaluated using d-optimal mixture experimental design and multilayer perceptron ANNs. Physicochemical characterization proved the presence of the most stable carbamazepine polymorph III within the SD matrix. Ternary carbamazepine-Soluplus®-poloxamer 188 SDs significantly improved carbamazepine dissolution rate compared to pure drug. Models developed by ANNs and mixture experimental design well described the relationship between proportions of SD components and percentage of carbamazepine released after 10 (Q10) and 20 (Q20) min, wherein ANN model exhibit better predictability on test data set. Proportions of carbamazepine and poloxamer 188 exhibited the highest influence on carbamazepine release rate. The highest carbamazepine release rate was observed for SDs with the lowest proportions of carbamazepine and the highest proportions of poloxamer 188. ANNs and mixture experimental design can be used as powerful data modeling tools in the systematic development of SDs. Taking into account advantages and disadvantages of both techniques, their combined application should be encouraged.

Dissolution rate enhancement and physicochemical characterization of carbamazepine-poloxamer solid dispersions.

This study investigates the potential of poloxamers as solid dispersions (SDs) carriers in improving the dissolution rate of a poorly soluble drug, carbamazepine (CBZ). Solid dispersions were prepared with poloxamer 188 (P188) and poloxamer 407 (P407) by melting method in different drug:carrier ratios (1:1, 1:2 and 1:3). Prepared samples were characterized using differential scanning calorimetry (DSC), hot-stage polarized light microscopy (HSM), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR) to investigate drug physical state within the SDs matrix, possible polymorphic transitions and drug-polymer interactions. The interactions between CBZ molecules and polymeric chains were also evaluated using molecular dynamics simulation (MDS) technique. The most thermodynamically stable polymorphic form III of CBZ was present in all SDs, regardless of the type of poloxamer and drug-to-carrier ratio. The absence of drug-polymer interactions was observed by FT-IR analysis and additionally confirmed by MDS. Formation of persistent hydrogen bond between two CBZ molecules, observed by MDS indicate high tendency of CBZ molecules to aggregate and form crystalline phase within dispersion. P188 exhibit higher efficiency in increasing CBZ dissolution rate due to its more pronounced hydrophilic properties, while increasing poloxamers concentration resulted in decreasing drug release rate, as a consequence of their thermoreversible gelation.

Model-Informed Drug Development: In Silico Assessment of Drug Bioperformance following Oral and Percutaneous Administration.

The pharmaceutical industry has faced significant changes in recent years, primarily influenced by regulatory standards, market competition, and the need to accelerate drug development. Model-informed drug development (MIDD) leverages quantitative computational models to facilitate decision-making processes. This approach sheds light on the complex interplay between the influence of a drug's performance and the resulting clinical outcomes. This comprehensive review aims to explain the mechanisms that control the dissolution and/or release of drugs and their subsequent permeation through biological membranes. Furthermore, the importance of simulating these processes through a variety of in silico models is emphasized. Advanced compartmental absorption models provide an analytical framework to understand the kinetics of transit, dissolution, and absorption associated with orally administered drugs. In contrast, for topical and transdermal drug delivery systems, the prediction of drug permeation is predominantly based on quantitative structure-permeation relationships and molecular dynamics simulations. This review describes a variety of modeling strategies, ranging from mechanistic to empirical equations, and highlights the growing importance of state-of-the-art tools such as artificial intelligence, as well as advanced imaging and spectroscopic techniques.

Spray coating as a powerful technique in preparation of solid dispersions with enhanced desloratadine dissolution rate.

Solid dispersion systems have been widely used to enhance dissolution rate and oral bioavailability of poorly water-soluble drugs. However, the formulation process development and scale-up present a number of difficulties which has greatly limited their commercial applications. In this study, solid dispersions (SDs) of desloratadine (DSL) with povidone (PVP) and crospovidone (cPVP) were prepared by spray coating technique. The process involved the spray application of 96% ethanol solution of DSL and PVP/cPVP, and subsequent deposition of the coprecipitates onto microcrystalline cellulose pellets during drying by air flow in a mini spray coater. The results from the present study demonstrated that the spray coating process is efficient in preparing SDs with enhanced drug dissolution rate and it is highly efficient in organic solvent removal. Both PVP and cPVP greatly improved drug dissolution rate by SDs, with PVP showing better solubilization capability. Very fast drug dissolution rate is achieved from SDs containing PVP regardless of differences in K grade. SD with smaller particles of cPVP have higher drug dissolution rate in comparison to the cPVP with larger particles. Results from physical state characterization indicate that DSL in SDs exist in the amorphous (high free-energy) state which is probably stabilized by PVP/cPVP. After 6-month accelerated stability study, DSL remains amorphous, while PVP and cPVP act as anti-plasticizing agents, offering efficient steric hindrance for nucleation and crystal growth.

Application of Machine-Learning Algorithms for Better Understanding the Properties of Liquisolid Systems Prepared with Three Mesoporous Silica Based Carriers.

The processing of liquisolid systems (LSS), which are considered a promising approach to improving the oral bioavailability of poorly soluble drugs, has proven challenging due to the relatively high amount of liquid phase incorporated within them. The objective of this study was to apply machine-learning tools to better understand the effects of formulation factors and/or tableting process parameters on the flowability and compaction properties of LSS with silica-based mesoporous excipients as carriers. In addition, the results of the flowability testing and dynamic compaction analysis of liquisolid admixtures were used to build data sets and develop predictive multivariate models. In the regression analysis, six different algorithms were used to model the relationship between tensile strength (TS), the target variable, and eight other input variables. The AdaBoost algorithm provided the best-fit model for predicting TS (coefficient of determination = 0.94), with ejection stress (ES), compaction pressure, and carrier type being the parameters that influenced its performance the most. The same algorithm was best for classification (precision = 0.90), depending on the type of carrier used, with detachment stress, ES, and TS as variables affecting the performance of the model. Furthermore, the formulations with Neusilin® US2 were able to maintain good flowability and satisfactory values of TS despite having a higher liquid load compared to the other two carriers.

Design space approach in optimization of fluid bed granulation and tablets compression process.

The aim of this study was to optimize fluid bed granulation and tablets compression processes using design space approach. Type of diluent, binder concentration, temperature during mixing, granulation and drying, spray rate, and atomization pressure were recognized as critical formulation and process parameters. They were varied in the first set of experiments in order to estimate their influences on critical quality attributes, that is, granules characteristics (size distribution, flowability, bulk density, tapped density, Carr's index, Hausner's ratio, and moisture content) using Plackett-Burman experimental design. Type of diluent and atomization pressure were selected as the most important parameters. In the second set of experiments, design space for process parameters (atomization pressure and compression force) and its influence on tablets characteristics was developed. Percent of paracetamol released and tablets hardness were determined as critical quality attributes. Artificial neural networks (ANNs) were applied in order to determine design space. ANNs models showed that atomization pressure influences mostly on the dissolution profile, whereas compression force affects mainly the tablets hardness. Based on the obtained ANNs models, it is possible to predict tablet hardness and paracetamol release profile for any combination of analyzed factors.

Health Benefits and Applications of Goji Berries in Functional Food Products Development: A Review.

Goji berries have long been used for their nutritional value and medicinal purposes in Asian countries. In the last two decades, goji berries have become popular around the world and are consumed as a functional food due to wide-range bioactive compounds with health-promoting properties. In addition, they are gaining increased research attention as a source of functional ingredients with potential industrial applications. This review focuses on the antioxidant properties of goji berries, scientific evidence on their health effects based on human interventional studies, safety concerns, goji berry processing technologies, and applications of goji berry-based ingredients in developing functional food products.

Improving Tableting Performance of Lactose Monohydrate by Fluid-Bed Melt Granulation Co-Processing.

Co-processing is commonly used approach to improve functional characteristics of pharmaceutical excipients to become suitable for tablet production by direct compression. This study aimed to improve tableting characteristics of lactose monohydrate (LMH) by co-processing by fluid-bed melt granulation with addition of hydrophilic (PEG 4000 and poloxamer 188) and lipophilic (glyceryl palmitostearate) meltable binders. In addition to binding purpose, hydrophilic and lipophilic excipients were added to achieve self-lubricating properties of mixture. Co-processed mixtures exhibit superior flow properties compared to pure LMH and comparable or better flowability relative to commercial excipient Ludipress®. Compaction of mixtures co-processed with 20% PEG 4000 and 20% poloxamer 188 resulted in tablets with acceptable tensile strength (>2 MPa) and good lubricating properties (ejection and detachment stress values below 5 MPa) in a wide range of compression pressures. While the best lubricating properties were observed when glyceryl palmitostearate was used as meltable binder, obtained tablets failed to fulfil required mechanical characteristics. Although addition of meltable binder improves interparticle bonding, disintegration time was not prolonged compared to commercial excipient Ludipress®. Co-processed mixtures containing 20% of either PEG 4000 or poloxamer 188 showed superior tabletability and lubricant properties relative to LMH and Ludipress® and can be good candidates for tablet production by direct compression.

Application of Machine-Learning Algorithms for Better Understanding of Tableting Properties of Lactose Co-Processed with Lipid Excipients.

Co-processing (CP) provides superior properties to excipients and has become a reliable option to facilitated formulation and manufacturing of variety of solid dosage forms. Development of directly compressible formulations with high doses of poorly flowing/compressible active pharmaceutical ingredients, such as paracetamol, remains a great challenge for the pharmaceutical industry due to the lack of understanding of the interplay between the formulation properties, process of compaction, and stages of tablets' detachment and ejection. The aim of this study was to analyze the influence of the compression load, excipients' co-processing and the addition of paracetamol on the obtained tablets' tensile strength and the specific parameters of the tableting process, such as (net) compression work, elastic recovery, detachment, and ejection work, as well as the ejection force. Two types of neural networks were used to analyze the data: classification (Kohonen network) and regression networks (multilayer perceptron and radial basis function), to build prediction models and identify the variables that are predominantly affecting the tableting process and the obtained tablets' tensile strength. It has been demonstrated that sophisticated data-mining methods are necessary to interpret complex phenomena regarding the effect of co-processing on tableting properties of directly compressible excipients.

Mucoadhesive buccal tablets with propranolol hydrochloride: Formulation development and in vivo performances in experimental essential hypertension.

The objective of this study was to formulate extended-release mucoadhesive buccal tablets of propranolol hydrochloride in order to provide a prolonged absorption of propranolol hydrochloride from the buccal mucosa and to reduce presystemic metabolism and thus provide a better therapeutic effect. Besides, the aim was to perform comparative in vivo pharmacokinetic and hemodynamic studies of the developed extended-release (ER) propranolol hydrochloride 10 mg mucoadhesive buccal tablets and commercial immediate-release (IR) propranolol hydrochloride 10 mg tablets in spontaneously hypertensive rats. Formulation with 15% polyethylene oxide showed the highest degree of propranolol hydrochloride permeation, satisfactory mucoadhesiveness, and extended-release of propranolol hydrochloride, thus it was selected for further in vivo study. The pharmacokinetic study in rats showed the superiority of ER mucoadhesive buccal tablets over IR tablets in terms of propranolol hydrochloride absorption extent (AUC values: 70.32 ± 19.56 versus 31.69 ± 6.97 µg·h/mL), although lower maximum plasma propranolol hydrochloride concentration (Cmax) was achieved. However, no statistically significant difference was observed in Cmax between these treatments. The hemodynamic study showed that ER mucoadhesive buccal tablets provide a more pronounced decrease primarily in heart rate, but also in systolic and diastolic arterial pressure, as well as a longer heart rate reduction compared to IR tablets.

Analytical and Computational Methods for the Estimation of Drug-Polymer Solubility and Miscibility in Solid Dispersions Development.

The development of stable solid dispersion formulations that maintain desired improvement of drug dissolution rate during the entire shelf life requires the analysis of drug-polymer solubility and miscibility. Only if the drug concentration is below the solubility limit in the polymer, the physical stability of solid dispersions is guaranteed without risk for drug (re)crystallization. If the drug concentration is above the solubility, but below the miscibility limit, the system is stabilized through intimate drug-polymer mixing, with additional kinetic stabilization if stored sufficiently below the mixture glass transition temperature. Therefore, it is of particular importance to assess the drug-polymer solubility and miscibility, to select suitable formulation (a type of polymer and drug loading), manufacturing process, and storage conditions, with the aim to ensure physical stability during the product shelf life. Drug-polymer solubility and miscibility can be assessed using analytical methods, which can detect whether the system is single-phase or not. Thermodynamic modeling enables a mechanistic understanding of drug-polymer solubility and miscibility and identification of formulation compositions with the expected formation of the stable single-phase system. Advance molecular modeling and simulation techniques enable getting insight into interactions between the drug and polymer at the molecular level, which determine whether the single-phase system formation will occur or not.

Optimization and Prediction of Ibuprofen Release from 3D DLP Printlets Using Artificial Neural Networks.

The aim of this work was to investigate effects of the formulation factors on tablet printability as well as to optimize and predict extended drug release from cross-linked polymeric ibuprofen printlets using an artificial neural network (ANN). Printlets were printed using digital light processing (DLP) technology from formulations containing polyethylene glycol diacrylate, polyethylene glycol, and water in concentrations according to D-optimal mixture design and 0.1% w/w riboflavin and 5% w/w ibuprofen. It was observed that with higher water content longer exposure time was required for successful printing. For understanding the effects of excipients and printing parameters on drug dissolution rate in DLP printlets two different neural networks were developed with using two commercially available softwares. After comparison of experimental and predicted values of in vitro dissolution at the corresponding time points for optimized formulation, the R2 experimental vs. predicted value was 0.9811 (neural network 1) and 0.9960 (neural network 2). According to difference f1 and similarity factor f2 (f1 = 14.30 and f2 = 52.15) neural network 1 with supervised multilayer perceptron, backpropagation algorithm, and linear activation function gave a similar dissolution profile to obtained experimental results, indicating that adequate ANN is able to set out an input-output relationship in DLP printing of pharmaceutics.

Selection of the suitable polymer for supercritical fluid assisted preparation of carvedilol solid dispersions.

Solid dispersions production is one of the substantial approaches for improvement of poor drug solubility. Additionally, supercritical fluid assisted method for preparation of solid dispersions can offer many advantages in comparison to the conventional melting or solvent-evaporation methods. Miscibility analysis provides valuable guidance for selection of the most appropriate polymeric carrier for dispersion of the drug of interest. In addition to the increased drug release rate, solid dispersions should have proper mechanical attributes in order to be successfully formulated in the final solid dosage form such as tablet. Therefore, several pharmaceutical grade polymers have been selected for development of BCS Class II drug carvedilol (CARV) solid dispersions. They were compared based on behavior in supercritical CO2 and affinity towards CARV calculated from the miscibility analysis. By utilization of the supercritical CO2 assisted method, solid dispersions of CARV with the selected (co)polymers (polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), Soluplus® and Eudragit®) were obtained. Properties of the prepared CARV-polymer dispersions were observed by the polarizing and scanning electron microscopy and analyzed by differential scanning calorimetry and Fourier transform infrared spectroscopy. CARV was additionally characterized by X-ray powder diffraction. Furthermore, in vitro dissolution studies and dynamic compaction analysis were performed on the selected samples of solid dispersions. Among the studied polymers, PVP and HPMC have been identified as polymers with the highest affinity towards CARV, based on the calculated δp values. This has been also confirmed with the highest dissolution efficiency of CARV-PVP and CARV-HPMC solid dispersions. Solid state characterization indicated that CARV was dispersed either molecularly, or in the amorphous form, depending on interactions with each polymer. Determination of CARV-PVP and CARV-HPMC mechanical properties revealed that CARV-PVP solid dispersion has superior compactibility and tabletability. Therefore, CARV-PVP solid dispersion has been highlighted as the most appropriate for the further development of tablets as the final dosage form. Presented study provides an example for efficient approach for development of poorly soluble drug solid dispersion with satisfactory tableting properties.

Intraoral administration of probiotics and postbiotics: An overview of microorganisms and formulation strategies

Abstract The last decade provided significant advances in the understanding of microbiota and its role in human health. Probiotics are live microorganisms with proven benefits for the host and were mostly studied in the context of gut health, but they can also confer significant benefits for oral health, mainly in the treatment of gingivitis. Postbiotics are cell-free extracts and metabolites of microorganisms which can provide additional preventive and therapeutic value for human health. This opens opportunities for new preventive or therapeutic formulations for oral administration. The microorganisms that colonize the oral cavity, their role in oral health and disease, as well as the probiotics and postbiotics which could have beneficial effects in this complex environment were discussed. The aim of this study was to review, analyse and discuss novel probiotic and postbiotic formulations intended for oral administration that could be of great preventive and therapeutic importance. A special attention has been put on the formulation of the pharmaceutical dosage forms that are expected to provide new benefits for the patients and technological advantages relevant for industry. An adequate dosage form could significantly enhance the efficiency of these products.

Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling.

The aim of this study is to develop nanosuspension of carvedilol (CRV) by wet media milling. Concentration of polymeric stabilizer (hydroxypropyl cellulose-HPC-SL), milling speed and size of milling beads were identified as critical formulation and process parameters and their effect on CRV particle size after 60 min of milling was assessed using a Box-Behnken experimental design. Optimized nanosuspension was solidified using spray drying and freeze drying and subjected to solid state characterization. Low stabilizer concentration (10%), low milling speed (300 rpm) with small milling beads (0.1 mm) were found as optimal milling conditions. Crystal lattice simulation identified potential slip plane within CRV crystals, where fractures are the most likely to occur. Calculated mechanical properties of CRV crystal indicates that low energy stress is sufficient to initiate fracture, if applied in the correct direction, explaining the advantage of using smaller milling beads. Only spray dried nanosuspension redispersed to original nanoparticles, while particle agglomeration during freeze drying prevented sample redispersion. Wet milling and spray drying did not induce polymorphic transition of CRV, while there is indication of polymorphic transition during freeze drying, making spray drying as the preferred solidification method.

Assessing the potential of solid dispersions to improve dissolution rate and bioavailability of valsartan: In vitro-in silico approach.

This study aimed to improve dissolution rate of valsartan in an acidic environment and consequently its oral bioavailability by solid dispersion formulation. Valsartan was selected as a model drug due to its low oral bioavailability (~23%) caused by poor solubility of this drug in the low pH region of gastrointestinal tract (GIT) and presence of absorption window in the upper part of GIT. Solid dispersions were prepared by solvent evaporation method with Eudragit® E100, Soluplus® or polyvinylpyrrolidone K25 (PVP K25) in drug:polymer weight ratios of 1:1, 1:2, 1:4 and 1:6 and further subjected to solid-state characterization and in vitro drug dissolution testing in 0.1 M HCl. The expected drug plasma concentration vs. time profiles after oral administration of the selected solid dispersion formulations were predicted using physiologically-based in silico modeling. Fast and complete dissolution of valsartan, with >80% of dissolved drug within the first 10 min of testing, was observed only from solid dispersions prepared with Eudragit® E100 in drug:polymer ratios of 1:2, 1:4 and 1:6. In all other samples, valsartan dissolution was slow and incomplete. Solid-state characterization showed amorphous nature of both pure drug and solid dispersion samples, as well as favourable intermolecular interactions between valsartan and polymers over interactions between drug molecules. The constructed in silico model predicted >40% of increase in valsartan bioavailability, Cmax and AUC values from selected solid dispersion formulations compared to conventional solid oral dosage form such as IR capsules. Based on the results of the in vitro-in silico study, formulation of solid dispersions of valsartan with Eudragit® E100 polymer can be considered as a promising approach for improving valsartan bioavailability.

Dry powder inhalers: An overview of the in vitro dissolution methodologies and their correlation with the biopharmaceutical aspects of the drug products.

In vitro dissolution testing is routinely used in the development of pharmaceutical products. Whilst the dissolution testing methods are well established and standardized for oral dosage forms, i.e. tablets and capsules, there are no pharmacopoeia methods or regulatory requirements for testing the dissolution of orally inhaled powders. Despite this, a wide variety of dissolution testing methods for orally inhaled powders has been developed and their bio-relevance has been evaluated. This review provides an overview of the in vitro dissolution methodologies for dry inhalation products, with particular emphasis on dry powder inhalers, where the dissolution behavior of the respirable particles can have a role on duration and absorption of the drug. Dissolution mechanisms of respirable particles as well as kinetic models have been presented. A more recent biorelevant dissolution set-ups and media for studying inhalation biopharmaceutics were also reviewed. In addition, factors affecting interplay between dissolution and absorption of deposited particles in the context of biopharmaceutical considerations of inhalation products were examined.

Modeling in the quality by design environment: Regulatory requirements and recommendations for design space and control strategy appointment.

Mathematical models can be used as an integral part of the quality by design (QbD) concept throughout the product lifecycle for variety of purposes, including appointment of the design space and control strategy, continual improvement and risk assessment. Examples of different mathematical modeling techniques (mechanistic, empirical and hybrid) in the pharmaceutical development and process monitoring or control are provided in the presented review. In the QbD context, mathematical models are predominantly used to support design space and/or control strategies. Considering their impact to the final product quality, models can be divided into the following categories: high, medium and low impact models. Although there are regulatory guidelines on the topic of modeling applications, review of QbD-based submission containing modeling elements revealed concerns regarding the scale-dependency of design spaces and verification of models predictions at commercial scale of manufacturing, especially regarding real-time release (RTR) models. Authors provide critical overview on the good modeling practices and introduce concepts of multiple-unit, adaptive and dynamic design space, multivariate specifications and methods for process uncertainty analysis. RTR specification with mathematical model and different approaches to multivariate statistical process control supporting process analytical technologies are also presented.