The comparison of melt technologies based on mesoporous carriers for improved carvedilol dissolution.

High-shear (HS) melt granulation and hot melt extrusion (HME) were compared as perspective melt-based technologies for preparation of amorphous solid dispersions (ASDs). ASDs were prepared using mesoporous carriers (SyloidⓇ 244FP or NeusilinⓇ US2), which were loaded with carvedilol dispersed in polymeric matrix (polyethylene glycol 6000 or SoluplusⓇ). Formulations with high carvedilol content were obtained either by HME (11 extrudates with polymer:carrier ratio 1:1) or HS granulation (6 granulates with polymer:carrier ratio 3:1). DSC and XRD analysis confirmed the absence of crystalline carvedilol for the majority of prepared ADSs, thus confirming the stabilizing effect of selected polymers and carriers over amorphous carvedilol. HME produced larger particles compared to HS melt granulation, which was in line with better flow time and Carr index of extrudates. Moreover, SEM images revealed smoother surface of ASDs obtained by HME, contributing to less obstructed flow. The rougher and more porous surface of HS granules was correlated to larger granule specific surface area, manifesting in faster carvedilol release from SyloidⓇ 244FP-based granules, as compared to their HME counterparts. Regarding dissolution, the two HS-formulations performed superior to pure crystalline carvedilol, thereby confirming the suitability of HS melt granulation for developing dosage forms with improved carvedilol dissolution.

Development of Orodispersible Tablets with Solid Dispersions of Fenofibrate and Co-Processed Mesoporous Silica for Improved Dissolution.

Poor water solubility is an important challenge in the development of oral patient-friendly solid dosage forms. This study aimed to prepare orodispersible tablets with solid dispersions of a poorly water-soluble drug fenofibrate and a co-processed excipient consisting of mesoporous silica and isomalt. This co-processed excipient, developed in a previous study, exhibited improved flow and compression properties compared to pure silica while maintaining a high specific surface area for drug adsorption. Rotary evaporation was used to formulate solid dispersions with different amounts of fenofibrate, which were evaluated for solid state properties and drug release. The solid dispersion with 30% fenofibrate showed no signs of crystallinity and had a significantly improved dissolution rate, making it the optimal sample for formulation or orodispersible tablets. The aim was to produce tablets with minimal amounts of additional excipients while achieving a drug release profile similar to the uncompressed solid dispersion. The compressed formulations met the requirements for orodispersible tablets in terms of disintegration time, and the drug release from best formulation approximated the profile of uncompressed solid dispersion. Future research should focus on reducing the disintegration time and tablet size to enhance patient acceptability further.

Investigating the Influence of Processing Conditions on Dissolution and Physical Stability of Solid Dispersions with Fenofibrate and Mesoporous Silica.

The study aimed to enhance the solubility of the poorly water-soluble drug, fenofibrate, by loading it onto mesoporous silica, forming amorphous solid dispersions. Solid dispersions with 30% fenofibrate were prepared using the solvent evaporation method with three solvents (ethyl acetate, acetone, and isopropanol) at different temperatures (40 °C, boiling point temperature). Various characteristics, including solid-state properties, particle morphology, and drug release, were evaluated by different methods and compared to a pure drug and a physical mixture of fenofibrate and silica. Results revealed that higher solvent temperatures facilitated complete amorphization and rapid drug release, with solvent choice having a lesser impact. The optimal conditions for preparation were identified as ethyl acetate at boiling point temperature. Solid dispersions with different fenofibrate amounts (20%, 25%, 35%) were prepared under these conditions. All formulations were fully amorphous, and their dissolution profiles were comparable to the formulation with 30% fenofibrate. Stability assessments after 8 weeks at 40 °C and 75% relative humidity indicated that formulations prepared with ethyl acetate and at 40 °C were physically stable. Interestingly, some formulations showed improved dissolution profiles compared to initial tests. In conclusion, mesoporous silica-based solid dispersions effectively improved fenofibrate dissolution and demonstrated good physical stability if prepared under appropriate conditions.

Taste-masking methods in multiparticulate dosage forms with a focus on poorly soluble drugs.

In the past, the administration of medicines for children mainly involved changes to adult dosage forms, such as crushing tablets or opening capsules. However, these methods often led to inconsistent dosing, resulting in under- or overdosing. To address this problem and promote adherence, numerous initiatives, and regulatory frameworks have been developed to develop more child-friendly dosage forms. In recent years, multiparticulate dosage forms such as mini-tablets, pellets, and granules have gained popularity. However, a major challenge that persists is effectively masking the bitter taste of drugs in such formulations. This review therefore provides a brief overview of the current state of the art in taste masking techniques, with a particular focus on taste masking by film coating. Methods for evaluating the effectiveness of taste masking are also discussed and commented on. Another important issue that arises frequently in this area is achieving sufficient dissolution of poorly water-soluble drugs. Since the simultaneous combination of sufficient dissolution and taste masking is particularly challenging, the second objective of this review is to provide a critical summary of studies dealing with multiparticulate formulations that are tackling both of these issues.

Evaluation of Monolayer and Bilayer Buccal Films Containing Metoclopramide.

The objective of this study was to develop buccal film formulations containing metoclopramide hydrochloride monohydrate (MCP) with and without a backing layer and to evaluate their release properties and physiochemical stability. The crystallization of MCP in the polymer matrix was monitored with image analysis techniques for rapid and scalable observation. The results showed that the addition of a protective layer and its thickness significantly affected the release rate and crystallization behavior of MCP in the formulations. The crystallization of MCP increased over time, and certain formulations showed higher susceptibility to crystallization. To understand the factors affecting the crystallization of MCP, the relationship between the viscosity and pH of the casting solution was examined, but no significant correlation was found. A significant correlation was observed between the plasticizer concentration and the physical state of MCP. Through a systematic Design of Experiment (DOE) approach, an optimal formulation was devised, successfully preventing crystallization of the active ingredient. However, enhancing the overall chemical stability of the formulated product remains a challenge.

Freeze-dried nanocrystal dispersion of novel deuterated pyrazoloquinolinone ligand (DK-I-56-1): Process parameters and lyoprotectant selection through the stability study.

Recently, nanocrystal dispersions have been considered as a promising formulation strategy to improve the bioavailability of the deuterated pyrazoloquinolinone ligand DK-I-56-1 (7­methoxy-2-(4­methoxy-d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one). In the current study, the freeze-drying process (formulation and process parameters) was investigated to improve the storage stability of the previously developed formulation. Different combinations of lyoprotectant (sucrose or trehalose) and bulking agent (mannitol) were varied while formulations were freeze-dried under two conditions (primary drying at -10 or -45 °C). The obtained lyophilizates were characterized in terms of particle size, solid state properties and morphology, while the interactions within the samples were analyzed by Fourier transform infrared spectroscopy. In the preliminary study, three formulations were selected based on the high redispersibility index values (around 95%). The temperature of primary drying had no significant effect on particle size, but stability during storage was impaired for samples dried at -10 °C. Samples dried at lower temperature were more homogeneous and remained stable for three months. It was found that the optimal ratio of sucrose or trehalose to mannitol was 3:2 at a total concentration of 10% to achieve the best stability (particle size < 1.0 µm, polydispersity index < 0.250). The amorphous state of lyoprotectants probably provided a high degree of interaction with nanocrystals, while the crystalline mannitol provided an elegant cake structure. Sucrose was superior to trehalose in maintaining particle size during freeze-drying, while trehalose was more effective in keeping particle size within limits during storage. In conclusion, results demonstrated that the appropriate combination of sucrose/trehalose and mannitol together with the appropriate selection of lyophilization process parameters could yield nanocrystals with satisfactory stability.

Effect of process parameters in high shear granulation on characteristics of a novel co-processed mesoporous silica material.

In this study, insights into the development and optimization of a co-processed excipient based on mesoporous silica are presented. The main advantage of such a material is that it is appropriate for direct tablet compression and has a sufficiently large specific surface area to be suitable for potential subsequent drug loading and formulation of (amorphous) solid dispersions. Our aim was to use a Design of Experiments approach to investigate which process parameters in high shear granulation affect the characteristics of such a co-processed material. The parameters included were the amount of binder (isomalt), the amount of water (granulation liquid), the water addition rate and the speed of the impeller. The responses evaluated and modelled were particle size and its distribution, specific surface area, bulk density, flowability, compressibility and compactibility. The models obtained showed good quality in terms of goodness of fit and predictive power. Active effects were identified for all responses, giving a thorough insight into factors affecting the material characteristics. Optimization experiments resulted in products with the desired characteristics (high specific surface area, large particle size, good flow and compression properties) and confirmed the validity of the generated models.

Formulation and Characterization of Buccal Films Containing Valsartan with Additional Support from Image Analysis.

The present study was aimed to the development and characterization of valsartan-containing buccal films with an introduction to a novel technique of image analysis. Visual inspection of the film provided a wealth of information that was difficult to quantify objectively. The obtained images of the films observed under the microscope were embedded in a convolutional neural network (CNN). The results were clustered according to their visual quality and on the basis of data distances. Image analysis proved to be a promising method to characterize buccal films appearance and their visual properties. The differential behavior of film composition was investigated using a reduced combinatorial experimental design. Formulation properties such as dissolution rate, moisture content, valsartan particle size distribution, film thickness, and drug assay were evaluated. In addition, more advanced methods such as Raman microscopy and image analysis were used to characterize the developed product in more detail. The results of dissolution tests using four different dissolution apparatuses showed a significant difference between the formulations containing the active ingredient in different polymorphic states. The dynamic contact angle of a water droplet on the surface of the films was measured, which correlated well with the dissolution times at 80% of the released drug (t80).

Spherical Agglomerates of Lactose Reduce Segregation in Powder Blends and Improve Uniformity of Tablet Content at High Drug Loads.

We report here on improved uniformity of blends of micronised active pharmaceutical ingredients (APIs) using addition of spherical agglomerates of lactose and enhanced blend flow to improve tablet content uniformity with higher API loads. Micromeritic properties and intra-particle porosity (using nano-computed X-ray tomography) of recently introduced spherical agglomerates of lactose and two standard lactose grades for the direct compression processes were compared. Powder blends of the individual lactose types and different micronised API drug loads were prepared and subjected to specific conditions that can induce API segregation. Tablet content uniformity during direct compression was related to the lactose material attributes. The distinctive micromeritic properties of the lactose types showed that spherical agglomerates of lactose had high intra-particle porosity and increased specific surface area. The stability of binary blends after intense sieving was governed by the intra-particle porosity and surface roughness of the lactose particles, which determined the retention of the model substance. Greater intra-particle porosity, powder specific surface area, and particle size of the spherical agglomerates provided greater adhesion of micronised particles, compared to granulated and spray-dried lactose. Thus the spherical agglomerates provided enhanced final blend flow and uniformity of tablet content at higher drug loads.

Application of commercially available mesoporous silica for drug dissolution enhancement in oral drug delivery.

Due to the high number of poorly water-soluble active pharmaceutical ingredients, oral drug delivery development has become challenging. One of the strategies to enhance drug solubility and to achieve high oral bioavailability is to formulate such compounds into amorphous solid dispersions. In recent years, porous materials have been investigated as possible carriers into which a drug can be adsorbed, such as mesoporous silica, in particular. Unlike the ordered mesoporous network of silica, non-ordered silica already has a "generally regarded as safe" status, and is already used as an excipient in pharmaceutical and cosmetic products. Thus, it is reasonable to expect that products that contain solid dispersions with non-ordered carriers will reach the market sooner and more easily than those with ordered mesoporous carriers. The emphasis of this review is therefore on non-ordered commercially available mesoporous silica and the progress that has been made in development of the use of these materials for improved dissolution rates in oral drug delivery. First, a thorough categorisation of the drug loading methods is presented, followed by discussion on the most important characteristics of solid dispersions (i.e., physical state, stability, drug release). Finally, manufacturability and production of a final solid dosage form are considered.

A straw for paediatrics: How to administer highly dosed, bitter tasting paracetamol granules.

Paediatric practice requires various dosing forms that are acceptable for children of different ages and abilities. A straw prefilled with a drug formulation might serve as a dosing form, especially for children and patients with swallowing difficulties. Using a two-step procedure, we developed granulated coated particles of bitter tasting paracetamol that are appropriate for use in a newly developed straw with two valves to assure liquid flow towards the oral cavity. The paracetamol crystals were coated with five different polymers (water-soluble, entero-soluble) to assure the duration of the taste-masking properties for several minutes during sipping of the drug. As none of these polymer coats assured small enough liquid volumes needed to empty the straw (20 mL) or low enough vacuum for easy drug consumption (130 mbar), the coated crystals were granulated with trehalose-erythritol powder mixture. Acceptable results were obtained with these granulated coated paracetamol particles when polyvinyl alcohol/polyethylene glycol graft copolymer (Kollicoat IR) or a mixture of this polymer with polyvinyl alcohol (Kollicoat Protect) were used. Dissolution tests in water and acidic media confirmed the taste-masking functionality of these particles during drinking simulation and immediate release of paracetamol in the stomach (85% in <30 min at pH 1.2, 4.5).

Spherical agglomerates of lactose as potential carriers for inhalation.

We report here on spherical lactose agglomerates as potential carriers for inhalation applications. Micromeritic properties of three spherical lactose agglomerates (SA-A, SA-B, SA-C) and a standard lactose inhalation grade carrier (Lactohale 100; LH100) were evaluated and compared. Ordered mixtures with micronized salbutamol sulfate as the model active pharmaceutical ingredient (API) and lactose carriers at two drug loadings (2 wt%, 5 wt%) were prepared, and in-vitro aerosolization performance was assessed. The spherical crystallization process led to particles with tailored micromeritic properties. These had larger specific surface area and greater fine fraction < 10 µm, compared to LH100, due to their coarse morphology. Their properties were reflected in the flowability parameters, where two types of spherical agglomerates of lactose showed more cohesive behavior compared to the other lactose grades. Blend uniformity showed improved homogeneous distribution of the API at higher drug load. In-vitro aerosolization tests showed that the spherical agglomerates of lactose enhanced the dose of API, compared to LH100. SA-B and SA-C showed significantly higher fine particle fractions at low drug load compared to the others, whereas overall, the largest fine particle fraction was for SA-B at high drug load. The carrier material attributes related to particle size, specific surface area, compressibility, flowability (cohesion, flow function), and air permeability were critical for aerosolization performance.

Design of Experiments for Optimization of the Lactose Spherical Crystallization Process.

This study provides a comprehensive assessment of the parameters of the spherical crystallization process and their impact on the micromeritic properties of lactose spherical agglomerates. A recently introduced definitive screening design was used to study various process parameters, with particular focus on building predictive models. The parameters included were: lactose solution concentration; volume ratio between the antisolvent and the whole crystallization system; crystallization system temperature; velocity of the addition of the lactose water solution; agitation velocity; and agitation time after whole addition of the lactose solution. Their effects on process yield, particle size parameters D10, D50 and D90, particle size distribution, morphological properties (roundness, solidity) and Hausner ratio were studied. Active effects were identified for all of these responses, with quadratic and interaction effects included. Lactose concentration, volume ratio, crystallization system temperature, and agitation velocity were identified as critical process parameters. For every response, a statistical model was built, where those for Hausner ratio, yield and roundness provided the best predictive performances. Based on these models, D10 and yield were successfully optimized. Definitive screening design proved as useful especially in the screening phase; however, additional experiments are needed to build models with high predictive power for all of these responses.

Advanced flow cell design for in vitro release testing of mucoadhesive buccal films.

Films for buccal application are a slowly emerging new platform for drug delivery. There remains a lack of analytical techniques for the determination of in vitro active pharmaceutical ingredient release. The aim here was to develop an alternative method to the commonly used United States Pharmacopoeia (USP) 2 method, based on the flow-through cell. This system extends the release time and enables more detailed sample discrimination according to formulation. It could be used as a tool for in vivo prediction of drug release rates from buccal film formulations. The flow cell contains two chambers separated by a membrane through which the released active pharmaceutical ingredient is measured. Vital system variables and their effects on the release rate of the model active pharmaceutical ingredient are presented for formulations based on sodium alginate polymer. The method reflects the differences between films and is shown to be discriminatory for evaluation of buccal formulations.

Excipients in freeze-dried biopharmaceuticals: Contributions toward formulation stability and lyophilisation cycle optimisation.

Biopharmaceuticals are one of the fastest growing areas within the pharmaceutical industry. As protein drugs require parenteral administration, they are commonly formulated as aqueous solutions. However, this is not always feasible due to their general instability. In such cases, lyophilised powders for injection are the dosage form of choice, for the preparation of stable products. Lyophilisation is known to be highly time and energy consuming, and hence it is an expensive technological process. Thus, the pharmaceutical industry is increasingly focused on its optimisation. Implementation of aggressive conditions, together with optimisation of formulation parameters, represent the contemporary approach to reduction of the primary drying time. As such, incorporation of drug-specific excipients can contribute significantly to the stability of a biologically active ingredient, and indirectly they can also affect the time needed for lyophilisation. The addition of the most relevant protein stabilisers, surfactants, buffers and bulking agents is therefore crucial. The main aim of the present review is to define the most important groups of biopharmaceutical excipients, based on their roles in formulations and the mechanism(s) through which they support the lyophilisation process, to provide products with the required protein efficiency and product characteristics. The scope of the article is to critically discuss the suitability of novel stabilizers, with higher critical temperatures and bulking agents in terms of implementation of aggressive primary drying. For better assignment of the topic-related challenges, the stabilities of biopharmaceutical drugs and the fundamentals of the lyophilisation process are also briefly described.

Elucidating molecular properties of kappa-carrageenan as critical material attributes contributing to drug dissolution from pellets with a multivariate approach.

Multivariate data analysis (MVDA) and artificial neural networks (ANN) are supporting statistical methodologies required for successful development and manufacturing of drug products. To address this purpose, a complex dataset from 49 industrially produced capsules filled with pellets was first analyzed through the development of a multiple linear regression model focused on determining raw material attributes or process parameters with a significant impact on drug dissolution. Based on the model, the following molecular and micrometrics properties of κ-carrageenan have been identified as critical material attributes with the highest contribution to drug dissolution: molecular weight and polydispersity index, viscosity, content of potassium ions, wettability, particle size, and density. The process parameters identified to control the drug dissolution behavior of pellets were amount of granulation liquid, torque of dry blend, spheronization parameters, and yields after screening. To further scrutinize the dataset, an ANN model was subsequently built, incorporating 29 batches addressing drug particle size and process parameters such as torque during granulation and spheronization time as critical factors. Finally, this study demonstrates the ability of MVDA and ANN to allow prediction of the key performance drivers influencing the drug dissolution of industrially developed capsules filled with pellets and it highlights their complementary relationship.

The formation and effect of mannitol hemihydrate on the stability of monoclonal antibody in the lyophilized state.

Crystalline bulking agent in lyophilized biopharmaceutical formulations provides an elegant lyophilized cake structure and allows aggressive primary drying conditions. The interplay between amorphous and crystalline state of excipients heavily influence the stability of lyophilized biological products and should be carefully evaluated in the formulation and process development phase. This study focuses on: (1) elucidating the influence of formulation and lyophilization process variables on the formation of different states of mannitol and (2) its impact on model monoclonal antibody stability when compared to sucrose. The main aim of the present research work was to study the influence of different mannitol to sucrose ratios and monoclonal antibody concentrations on mannitol physical form established during lyophilization. In addition, also the effect of process variables on mannitol hemihydrate (MHH) formation was under investigation. Thermal analysis and powder X-ray diffraction results revealed that the ratio between sucrose and mannitol and mAb concentration have a decisive impact on mannitol crystallization. Namely, increasing amount of mannitol and monoclonal antibody resulted in decreasing formation of MHH. From the process parameters investigated, a higher secondary drying temperature has the biggest impact on the complete dehydration of MHH. Specifically, higher secondary drying temperature reflected in complete dehydration of MHH. Annealing temperature was shown to affect the MHH content in the final product, wherein the higher annealing temperature was preferential for formation of anhydrous mannitol. Temperature stress stability study revealed that the most important parameter influencing monoclonal antibody stability is the ratio of protein to sucrose. Contrary to widespread assumption, we did not detect any impact of MHH on the stability of the investigated monoclonal antibody.

Matrix Tablets for Controlled Release of Drugs Incorporated Using Capillary Absorption.

Cost and time effectiveness make direct tableting still the favored method for tablet production. Among its most noticeable limitations in application is the non-uniformity (and/or inhomogeneities) in the contents of the resulting tablets, possibly leading to inconsistencies in required tablet properties. The efficiency of direct tableting is mostly affected by surface properties of the components to be tableted, which govern the final tablet mechanical and chemical properties and can influence the liquid capillary rise that the tablets exhibit after ingestion. By using capillary rise as a driving force, we developed a simple, yet powerful procedure for filling blank tablets with a repeatable drug amount. Blank tablets were prepared by direct compression of the excipient and filled with an organic solution of hydrochlorothiazide. Tablets were characterized regarding their structure and morphology, while their applicability was monitored using in vitro drug release studies. By utilizing the mentioned filling of blank tablets, we were able to incorporate the desired dose of the drug inside while maintaining the tablets initial mechanical properties. Moreover, most of the drug was incorporated in the tablet pores and the rest was homogeneously distributed over the tablet surface in the form of small particles, by which we also eliminated content non-uniformity (homogenous drug distribution through the tablet). To sum up, we not only developed a cheap, simple, and reproducible variation of direct tableting, but were also able to eliminate some of its biggest disadvantages (e.g., segregation of components, leading to inhomogeneities in contents, and incompatibility between different base ingredients due to their different surface properties). All mentioned make the proposed approach highly interesting for future use, especially in potential therapy individualization.

Modified equation for particle bonding area and strength with inclusion of powder fragmentation propensity.

The paper considers a novel, modified equation for evaluation of relationship between tablet tensile strength, bonding area and bonding strength with inclusion of fragmentation as particle deformation mechanism. Four types of lactose particles for direct compression were assessed for their micromeritic and mechanical properties (compressibility and compactibility), with particular focus on fragmentation behaviour, bonding area and bonding strength. Compressibility properties were assessed using three established models. Walker and Kuentz-Leuenberger models distinguished lactose plastic properties more effectively in contrast to the Heckel model. Spherical agglomerates of lactose were most prone to fragmentation as determined with the fragmentation propensity coefficient and the number of interparticulate bonds. Fragmentation, together with plastic deformation were found to be the governing factors for tablet tensile strength in α-lactose samples, while high bonding force primarily controlled the tablet tensile strength of anhydrous lactose. Tensile strength of all lactose tablets showed best correlation to the ratio of fragmentation propensity and Walker compressibility coefficient, which is proposed as better deformation index, intended to describe the overall deformation properties of lactose more precisely. A novel expression for determining bonding area is proposed, established on the enhanced deformation index, which includes both plastic deformation and fragmentation as bond formation mechanisms.

Novel Budesonide Particles for Dry Powder Inhalation Prepared Using a Microfluidic Reactor Coupled With Ultrasonic Spray Freeze Drying.

Budesonide (BDS) is a potent active pharmaceutical ingredient, often administered using respiratory devices such as metered dose inhalers, nebulizers, and dry powder inhalers. Inhalable drug particles are conventionally produced by crystallization followed by milling. This approach tends to generate partially amorphous materials that require post-processing to improve the formulations' stability. Other methods involve homogenization or precipitation and often require the use of stabilizers, mostly surfactants. The purpose of this study was therefore to develop a novel method for preparation of fine BDS particles using a microfluidic reactor coupled with ultrasonic spray freeze drying, and hence avoiding the need of additional homogenization or stabilizer use. A T-junction microfluidic reactor was employed to produce particle suspension (using an ethanol-water, methanol-water, and an acetone-water system), which was directly fed into an ultrasonic atomization probe, followed by direct feeding to liquid nitrogen. Freeze drying was the final preparation step. The result was fine crystalline BDS powders which, when blended with lactose and dispersed in an Aerolizer at 100 L/min, generated fine particle fraction in the range 47.6% ± 2.8% to 54.9% ± 1.8%, thus exhibiting a good aerosol performance. Subsequent sample analysis confirmed the suitability of the developed method to produce inhalable drug particles without additional homogenization or stabilizers. The developed method provides a viable solution for particle isolation in microfluidics in general.