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Apremilast (APST) is an effective inhibitor of phosphodieasterase 4 (PDE4) which is the first oral drug for the treatment of adult patients with active psoriatic arthritis. However, Apremilast's low solubility restricts its dissolution and bioavailability. In this study, APST solid dispersion with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and Poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA) was developed to improve the dissolution and bioavailability of APST by spray drying. A series of TPGS were synthesized to elucidate the effect of the ratio of monoester to diester on solubilizing capacity. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and Fourier transform infrared spectrophotometry (FT-IR) were used to characterize the solid dispersion, and the results showed that APST was amorphous in solid dispersion. In vitro dissolution study showed that the dissolution rate of solid dispersion in phosphate buffered saline (pH 6.8) was remarkably increased, reaching a release of 90% within 10 min. Moreover, in vivo pharmacokinetics study revealed that the bioavailability of solid dispersion in rats had significant improvement. In particular, its Cmax and AUClast were nearly 22- and 12.9-fold greater as compared to APST form B, respectively. In conclusion, APST solid dispersion with TPGS and PVPVA is an alternative drug delivery system to improve the solubility and oral bioavailability of APST.

The taste of drug substances plays a key role in the development of paediatric formulations with suitable organoleptic properties. The aim of the study was to evaluate the taste masking effectiveness of Smartseal 30D and ReadyMix on a range of bitter drug substances such as diphenhydramine HCl (DPD), ibuprofen lysine (IBU-LS), and phenylephrine HCl (PPH) for the development of paediatric dosage forms. The drugs were microencapsulated in the polymer carriers at 10-20% loadings using spray-drying processing. Spray drying of drug formulations was optimized in terms of percent yield and encapsulation efficiency followed by physicochemical characterization in order to identify the drugs' physical state in the polymer microparticles. The in vivo taste masking efficiency was evaluated using human test panel and showed noticeable reduction of drug's bitterness at all loadings in comparison to the bulk substances.

Several drugs have poor oral bioavailability due to low or incomplete absorption which is affected by various effects as pH, motility of GI, and enzyme activity. The gastroretentive drug delivery systems are able to deal with these problems by prolonging the gastric residence time, while increasing the therapeutic efficacy of drugs. Previously, we developed a novel technology to foam hot and molten dispersions on atmospheric pressure by a batch-type in-house apparatus. Our aim was to upgrade this technology by a new continuous lab-scale apparatus and confirm that our formulations are gastroretentive. At first, we designed and built the apparatus and continuous production was optimized using a Box–Behnken experimental design. Then, we formulated barium sulfate-loaded samples with the optimal production parameters, which was suitable for in vivo imaging analysis. In vitro study proved the low density, namely 507 mg/cm3, and the microCT record showed high porosity with 40 μm average size of bubbles in the molten suspension. The BaSO4-loaded samples showed hard structure at room temperature and during the wetting test, the complete wetting was detected after 120 min. During the in vivo study, the X-ray taken showed the retention of the formulation in the rat stomach after 2 h. We can conclude that with our device low-density floating formulations were prepared with prolonged gastric residence time. This study provides a promising platform for marketed active ingredients with low bioavailability.

For a dissolution method to be considered relevant to in vivo performance, the dissolution data profiles should show discrimination or meaningful change when there is a change in critical material attributes (CMAs) and critical product properties (CPPs). The dissolution test has been shown repeatedly to have the power to distinguish between significant changes in active pharmaceutical ingredient (API), formulation, and process that relate to the release mechanism of the in vivo performance. Examples will be discussed in the literature where the effects of formulation, drug substance, and manufacturing variables have been measured by dissolution testing. There will be a suggested plan on how to develop and challenge a discriminating method that may be utilized for regulatory purposes. A brief review of other challenges and considerations regarding discriminatory dissolution testing is presented.

In this study, an attempt was made to produce Liqui-Tablets for the first time. This was carried out through the compaction of naproxen Liqui-Pellets. The incentive to convert the novel Liqui-Pellet into Liqui-Tablet was due to the array of inherent advantages of the popular and preferred tablet dosage form. The study showed that naproxen Liqui-Tablet could be successfully produced and the rapid drug release rate (100% drug release ~ 20 min) could be achieved under pH 1.2, where naproxen is insoluble. It was observed that the different pH of the dissolution medium affected the trend of drug release from formulations with varying amounts of liquid vehicle. The order of the fastest drug-releasing formulations was different depending on the pH used. The presence of Neusilin US2 showed considerable enhancement in the drug release rate as well as improving Liqui-Tablet robustness and hardness. Furthermore, images from X-ray micro-tomography displayed a uniform distribution of components in the Liqui-Tablet. The accelerated stability studies showed acceptable stability in terms of dissolution profile.

Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.

The present study endeavored to develop orodispersible films (ODFs) containing 30 mg racecadotril for pediatric use, which focuses on improving the compliance of pediatric patients and reducing risk of choking. The challenge of this study is to prepare high drug loading ODFs with successful mechanical and physicochemical properties. Compatibilities between drug and different polymers (hydroxypropyl methylcellulose, HPMC; polyvinyl alcohol, PVA; low-substituted hydroxypropyl cellulose, L-HPC; pullulan, PU) were investigated to select stable and safe film-forming polymers. Afterwards, the study explored the maximum amount of racecadotril incorporated into PVA films and PU films. Subsequently, disintegrant (Lycoat RS720, 4–10%, w/w) and plasticizers (glycerol, 2–6%, w/w) were investigated to reduce disintegration time of PVA films and enhance the flexibility of PU films, respectively. Formulation characteristics (appearance, tensile strength, percent elongation, disintegration time, drug content, weight, thickness, pH value, moisture content, moisture uptake, and Q5min) of prepared ODFs were examined to obtain the optimal compositions of racecadotril ODFs. Differential scanning calorimetry (DSC) study, powder X-ray diffraction (XRD) study, Fourier transform infrared (FTIR) study, comparative in vitro dissolution study, and pharmacokinetic study in Beagle dogs of optimized racecadotril ODFs were then conducted. Eventually, ODFs containing 50% racecadotril, 38% PVA, 7% Lycoat RS720, 2% sucralose, 2% apricot, and 1% titanium dioxide could achieve desirable mechanical properties, disintegrating within a few seconds and releasing more than 85% drug within 5 min in four dissolution media. An in vivo study showed optimized racecadotril ODF and Hidrasec were bioequivalent in Beagle dogs. In summary, ODFs containing 30 mg racecadotril were successfully prepared by solvent casting method, and it was suitable for the administration to the pediatric patients.

Personalized medicine has the potential to revolutionize the healthcare sector, its goal being to tailor medication to a particular individual by taking into consideration the physiology, drug response, and genetic profile of that individual. There are many technologies emerging to cause this paradigm shift from the conventional “one size fits all” to personalized medicine, the major one being three-dimensional (3D) printing. 3D printing involves the establishment of a three-dimensional object, in a layer upon layer manner using various computer software. 3D printing can be used to construct a wide variety of pharmaceutical dosage forms varying in shape, release profile, and drug combination. The major technological platforms of 3D printing researched on in the pharmaceutical sector include inkjet printing, binder jetting, fused filament fabrication, selective laser sintering, stereolithography, and pressure-assisted microsyringe. A possible future application of this technology could be in a clinical setting, where prescriptions could be dispensed based on individual needs. This manuscript points out the various 3D printing technologies and their applications in research for fabricating pharmaceutical products, along with their pros and cons. It also presents its potential in personalized medicine by individualizing the dose, release profiles, and incorporating multiple drugs in a polypill. An insight on how it tends to various populations is also provided. An approach of how it can be used in a clinical setting is also highlighted. Also, various challenges faced are pointed out, which must be overcome for the success of this technology in personalized medicine.

In 2017, there are 451 million people with diabetes worldwide. These figures were expected to increase to 693 million by 2045. The research and development of hypoglycemic drugs has become a top priority. Among them, sulfonylurea hypoglycemic drugs such as glipizide are commonly used in non-insulin-dependent type II diabetes. In order to adapt to the wide range of hypoglycemic drugs and the different individual needs of patients, this topic used glipizide as a model drug, and prepared glipizide preparations with 3D printing technology. The purpose of this study was to investigate the prescription applicability and control-release behavior of structure and explore the application prospects of 3D printing personalized drug delivery formulations. This article aims to establish a production process for personalized preparations based on 3D printing technology. The process is easy to obtain excipients, universal prescriptions, flexible dosages, exclusive customization, and integrated automation. In this paper, the UV method was used to determine the in vitro release and content analysis method of glipizide; the physical and chemical properties of the glipizide were investigated. The established analysis method was inspected and evaluated, and the experimental results met the methodological requirements. Glipizide controlled-release tablets were prepared by the semisolid extrusion (SSE) method using traditional pharmaceutical excipients combined with 3D printing technology. The formulation composition, in vitro release, and printing process parameters of the preparation were investigated, and the final prescription and process parameters (traveling speed 6.0–7.7 mm/s and extruding speed 0.0060–0.0077 mm/s) were selected through comprehensive analysis. The routine analysis results of the preparation showed that the performance of the preparation meets the requirements. In order for 3D printing technology to play a better role in community medicine and telemedicine, this article further explored the universality of the above prescription and determined the scope of application of prescription drugs and dosages. Glipizide, gliclazide, lornoxicam, puerarin, and theophylline were used as model drugs, and the range of drug loading percentage was investigated. The results showed when the solubility of the drug is 9.45 –8.34 mg/mL, and the drug loading is 3–43%; the release behavior is similar.

The acceptability and palatability of a dosage form are extremely important to improve patient compliance. Mixing oral solid dosage forms with food carriers is often necessary to ease swallowing and provide the taste-masking effect. The present research investigated how a liquid or semisolid carrier influences the disintegration time and drug dissolution rate of pellets and minitablets with diazepam. The disintegration of pellets and minitablets in liquid carriers (water, milk and apple juice) was determined using a texture analyser. Dissolution tests were performed for the dosage forms dispersed in gel vehicles (2% carmellose and 0.5% carbomer gels) or applesauce. The disintegration of minitablets in water and apple juice was fast (1 min), but it slowed to 3 and 5 min in milk and gel vehicles, respectively. The pellets disintegrated in liquid carriers within 3 min. The drug dissolution rate in 0.1 M HCl depended on the gel viscosity in this medium. The preserved high viscosity of a carmellose gel inhibited the dissolution of diazepam. On the other hand, the viscosity of the carbomer gel decreased rapidly, and in effect, the dissolution rate of diazepam from the incorporated pellets or minitablets was comparable to the dissolution from loose pellets or minitablets.

While polyethylene oxide (PEO)-based matrix tablets are frequently used as abuse-deterrent dosage forms, there is limited information available regarding how the selection of formulation components and manufacturing processes affect the resulting abuse-deterrent properties. The objective of the current study was to evaluate the effects of formulation and process variables on the abuse-deterrent features of PEO-containing tablets. Directly compressed tablets were prepared using three different PEO molecular weights (100,000; 900,000; and 5,000,000). As anticipated, sintering/thermal treatment above the melting point of PEO was crucial to impart crush-resistant features (tablet hardness > 500 N). In addition to the sintering temperature, the weight fraction of PEO in the tablets affected their mechanical strength, and at least 50% w/w PEO was required to impart the desired crush-resistant features. In addition, the formulation and process variables also impacted syringeability and injectability of the PEO gels formed when the tablets were hydrated to simulate attempted drug extraction. High molecular weight PEO (900,000 and 5,000,000) produced gels more resistant to syringeability and injectability compared to low molecular weight PEO (100,000). Sintering above the polymer melting point decreased PEO crystallinity after cooling, and longer sintering times resulted in PEO degradation producing lower viscosity gels with reduced resistance to syringeability and injectability. Although sintering above the melting point of PEO imparts optimal mechanical strength to the tablets, prolonged sintering durations negatively impact polymer stability and alter the resulting abuse-deterrent features of the PEO-based tablet formulations.

Our research group has pioneered the development of liquisolid pellets as a new drug delivery system targeting at the improvement of the dissolution rates of poorly water-soluble drugs, combining the technological and biopharmaceutical advantages of both multiparticulate and liquisolid systems. Recently, Lam and collaborators claimed the invention of "liqui-pellets" as "the emerging next-generation oral dosage form which stems from liquisolid concept in combination with pelletization technology". However, the concept of liqui-pellet is not novel. As we demonstrate in this commentary, liqui-pellets are the same type of preparation as our previously and extensively reported liquisolid pellets. Liquisolid pellets have been disclosed in a patent application and public peer-reviewed articles covering the concept, preparation and challenges associated with these systems. There are no technical differences that justify excluding our previous reports as the first reports on liquisolid pellets or liqui-pellets. This commentary highlights the similarities between liquisolid pellets and liqui-pellets, focusing on the anteriority of liquisolid pellets as disclosed by our group.

Due to the high number of poorly soluble drugs in the development pipeline, novel processes for delivery of these challenging molecules are increasingly in demand. One such emerging method is KinetiSol, which utilizes high shear to produce amorphous solid dispersions. The process has been shown to be amenable to difficult to process active pharmaceutical ingredients with high melting points, poor organic solubility, or sensitivity to heat degradation. Additionally, the process enables classes of polymers not conventionally processable due to their high molecular weight and/or poor organic solubility. Beyond these advantages, the KinetiSol process shows promise with other applications, such as the production of amorphous mucoadhesive dispersions for delivery of compounds that would also benefit from permeability enhancement.

Vemurafenib is a poorly soluble, low permeability drug that has a demonstrated need for a solubility-enhanced formulation. However, conventional approaches for amorphous solid dispersion production are challenging due to the physiochemical properties of the compound. A suitable and novel method for creating an amorphous solid dispersion, known as solvent-controlled coprecipitation, was developed to make a material known as microprecipitated bulk powder (MBP). However, this approach has limitations in its processing and formulation space. In this study, it was hypothesized that vemurafenib can be processed by KinetiSol into the same amorphous formulation as MBP. The KinetiSol process utilizes high shear to rapidly process amorphous solid dispersions containing vemurafenib. Analysis of the material demonstrated that KinetiSol produced amorphous, single-phase material with acceptable chemical purity and stability. Values obtained were congruent to analysis conducted on the comparator material. However, the materials differed in particle morphology as the KinetiSol material was dense, smooth, and uniform while the MBP comparator was porous in structure and exhibited high surface area. The particles produced by KinetiSol had improved in-vitro dissolution and pharmacokinetic performance for vemurafenib compared to MBP due to slower drug nucleation and recrystallization which resulted in superior supersaturation maintenance during drug release. In the in-vivo rat pharmacokinetic study, both amorphous solid dispersions produced by KinetiSol exhibited mean AUC values at least two-fold that of MBP when dosed as a suspension. It was concluded that the KinetiSol process produced superior dosage forms containing vemurafenib with the potential for substantial reduction in patient pill burden.

The use of amorphous solid dispersions to improve the bioavailability of active ingredients from the BCS II and IV classifications continues to gain interest in the pharmaceutical industry. Over the last decade, methods for generating amorphous solid dispersions have been well established in commercially available products and in the literature. However, the amorphous solid dispersions manufactured by different technologies differ in many aspects, primarily chemical stability, physical stability, and performance, both in vitro and in vivo. This review analyzes the impact of manufacturing methods on those properties of amorphous solid dispersions. For example, the chemical stability of drugs and polymers can be influenced by differences in the level of thermal exposure during fusion-based and solvent-based processes. The physical stability of amorphous content varies according to the thermal history, particle morphology, and nucleation process of amorphous solid dispersions produced by different methods. The in vitro and in vivo performance of amorphous formulations are also affected by differences in particle morphology and in the molecular interactions caused by the manufacturing method. Additionally, we describe the mechanism of manufacturing methods and the thermodynamic theories that relate to amorphous formulations.

Photodegradation is one of the major pathways of the degradation of drugs. Some therapeutic agents and excipients are highly sensitive to light and undergo significant degradation, challenging the quality and the stability of the final product. The adequate knowledge of photodegradation mechanisms and kinetics of photosensitive therapeutic entities or excipients is a pivotal aspect in the product development phase. Hence, various pharmaceutical regulatory agencies, across the world, mandated the industries to assess the photodegradation of pharmaceutical products from manufacturing stage till storage, as per the guidelines given in the International Conference on Harmonization (ICH). Recently, numerous formulation and/or manufacturing strategies has been investigated for preventing the photodegradation and enhancing the photostability of photolabile components in the pharmaceutical dosage forms. The primary focus of this review is to discuss various photodegradation mechanisms, rate kinetics, and the factors that influence the rate of photodegradation. We also discuss light-induced degradation of photosensitive lipids and polymers. We conclude with a brief note on different approaches to improve the photostability of photosensitive products.

Currently available antiulcer drugs suffered from serious side effects which limited their uses and prompted the need for a safe and efficient new antiulcer agent. The objective of this project work was to retain the drug in the stomach for better antiulcer activity and less side effects. Hence, the aim of our present work was to prepare a gastric floating tablet of Berberine hydrochloride (Ber) with suitable in vitro/vivo properties. In this study, different Ber gastric floating tablets were prepared by simple direct compression using various amounts of HPMCK15M and Carbopol 971PNF combined with other tablet excipients. The properties of the tablets including hardness, buoyancy, swelling ability, in vitro drug release, and in vivo pharmacokinetic study were evaluated. The obtained results disclosed that hardness, floating, swelling, and in vitro drug release of the Ber tablets depended mainly on the ratio of polymer combinations. Moreover, among six formulations, F3 exhibited desirable floating, swelling, and extended drug release. In addition, in vivo pharmacokinetic study suggested that prepared gastric floating tablets had significantly sustained-releasing effects compared with market tablets. Therefore, the developed gastric floating tablets of Ber could be an alternative dosage form for treatment of gastrointestinal disease.

In the study, we developed a novel oral dosage form of Compound Danshen to resolve the problems of low bioavailability, disequilibrium in drug release, and stomach degradation of active components of Compound Danshen in conventional formulas. A colon-specific osmotic pump capsule (COPC) of Compound Danshen was prepared using a semipermeable shell with the core components. Using a single-factor method, we obtained the optimal formulation that consisted of Salvia miltiorrhiza extract, Panax notoginseng extract, Borneol, sodium chloride, polyethylene oxide wsr-N10, hydroxypropyl-β-cyclodextrin, and ludipress. Moreover, in vitro dissolution test showed simultaneous releases of active ingredients from Compound Danshen COPC over 12 h at pH 7.8, displaying zero-order release characteristics. The impetus of drug release mainly depended on the difference in osmotic pressure across the capsule shell. Next, scanning electron microscopy showed morphological changes in the capsule shell during the dissolution test. More importantly, pharmacokinetic study in beagle dogs indicated that relative bioavailability was 330.58% and retention time was greatly prolonged in Compound Danshen COPC, compared with those in marketed Compound Danshen tablet products. Finally, in vivo imaging studies in beagle dogs showed that COPC was stable in gastrointestinal tract and the drug was specifically released in the colon region. A colon-specific osmotic pump capsule (COPC) of Compound Danshen was developed and optimized to achieve simultaneous zero-order release of multiple active components of Compound Danshen in the colon. More importantly, the COPC have proved to improve the bioavailability and prolong the retention time of Compound Danshen, compared with those in a marketed product.

Individualized dosing is often required in pharmacotherapy, particularly for pediatric and geriatric patients and adjustment of drugs that demand dose adaptation. This study aimed to evaluate critical quality attributes (CQAs) of doses obtained by distinct approaches for achieving individual dosing. Approaches were evaluated as follows: subdivision of tablets by splitter and hand (haloperidol) and delivery by plastic dropper bottle (haloperidol), glass dropper bottle (clonazepam), dosing cup (sodium valproate), and dosing syringe (carbamazepine), including brand name, generic, and similar marketed products. Measuring devices were packaged with their respective product. Drug content uniformity was assessed to each substance according to pharmacopeial methods. Tablets subdivided by splitter had the poorest performance among all approaches, in which doses ranged around 60% of the labeled amount (Acceptance Value = 58.1 and RSD = 23.2%). The greatest performances were observed for the dosing syringe which fulfilled all the requirements for dose precision and for the glass dropper bottle. There were significant differences in dose delivery between manufacturers of the same medicine when measuring the same volume or number of drops. High drug content variability is extremely harmful to pharmacotherapy and may result in therapeutic failure or toxicity. It is crucial that measuring devices and scoring of tablets be checked for functionality and standardized for different manufacturers of the same medicine. Part of the approaches for achieving individual dosing did not meet the quality needs for drug content and uniformity. Yet, our findings show that more accurate and precise dosing can be accessed when using the dosing syringe and glass dropper bottle.

Febuxostat suffers from relatively low bioavailability owing to the poor drug solubility and hepatic first-pass effect. This study aimed to prepare highly drug-loaded self-nanoemulsifying self-nanosuspension systems (SNESNS). SNESNS were designed to improve febuxostat's oral bioavailability by enhancing its solubility. Different oil and surfactant/co-surfactant mixtures were used for the preparation of SNESNS. The prepared SNESNS were estimated for their particle size, in vitro drug release and transmission electron microscopy (TEM). Results revealed that the oil mixture of Capryol™ 90:Miglyol® 812 (1:1 w/w) with surfactant/co-surfactant mixture of Cremophor® RH 40/Transcutol® HP loaded with drug in 4-fold greater concentration than its saturated solubility resulted in the formation of SNESNS by dilution under the effect of magnetic stirring. SNESNS were freeze-dried using trehalose as a cryoprotectant. TEM images and the bimodal particle size curve confirmed the formation of the biphasic nanosystems after dilution (nanoemulsion and nanosuspension). Higher Cmax and AUC0-48 values compared to those of the market product Feburic® tablets confirmed the success of the SNESNS as a promising carrier for drugs suffering from poor water solubility like febuxostat.

Dosage forms with increased gastric residence time are promising tools to increase bioavailability of drugs with narrow absorption window. Low-density floating formulations could avoid gastric emptying; therefore, sustained drug release can be achieved. Our aim was to develop a new technology to produce low-density floating formulations by melt foaming. Excipients were selected carefully, with the criteria of low gastric irritation, melting range below 70°C and well-known use in oral drug formulations. PEG 4000, Labrasol and stearic acid type 50 were used to create metronidazole dispersion which was foamed by air on atmospheric pressure using in-house developed apparatus at 53°C. Stearic acid was necessary to improve the foamability of the molten dispersion. Additionally, it reduced matrix erosion, thus prolonging drug dissolution and preserving hardness of the moulded foam. Labrasol as a liquid solubiliser can be used to increase drug release rate and drug solubility. Based on the SEM images, metronidazole in the molten foam remained in crystalline form. MicroCT scans with the electron microscopic images revealed that the foam has a closed-cell structure, where spherical voids have smooth inner wall, they are randomly dispersed, while adjacent voids often interconnected with each other. Drug release from all compositions followed Korsmeyer-Peppas kinetic model. Erosion of the matrix was the main mechanism of the release of metronidazole. Texture analysis confirmed that stearic acid plays a key role in preserving the integrity of the matrix during dissolution in acidic buffer. The technology creates low density and solid matrix system with micronsized air-filled voids.

An integrated approach based on QbD and PAT provides a systematic and innovative framework for product development, manufacturing, and quality risk management. In this context, the significance of the outcome of design of experiments (DOEs) to the selection of the product design, robust commercial manufacturing process, design space, and overall control strategy remains vital for the success of a drug product throughout its life cycle. This paper aims at discussing selected recent DOE case studies conducted during QbD-based and integrated QbD/PAT-based development of solid oral formulations and process improvement studies. The main focus of this paper is to highlight the rationales and importance of design selection during development and applications of mathematical models and statistical tools in analyzing DOE and PAT data for developing a design space, control strategy, and improved process monitoring. A total of 25 case studies (includes 9 PAT application studies) have been discussed in this paper which cover 11 manufacturing processes commonly utilized for solid dosage forms. Two case studies relevant to selection of packaging design for solid dosage forms are also briefly discussed to complete the scope. Overall, for a successful modern QbD approach, it is highly important that DOEs are conducted and analyzed in a logical sequence which involves designs that are phase-appropriate and quality-driven and facilitate both statistical and chemometric thinking at each development stage. This approach can result into higher regulatory flexibility along with lower economic burden during life cycle of a product, irrespective of regulatory path used (NDA or ANDA).

Corticosteroid resistance poses a major challenge to effective treatment of chronic obstructive pulmonary diseases. However, corticosteroid resistance can be overcome by co-administration of theophylline. The aim of this study was to formulate the corticosteroid budesonide with theophylline into inhalable dry powders intended for pulmonary combination therapy. Four types of spray-dried powders were prepared: (i) budesonide and theophylline co-dissolved and processed using a 2-fluid nozzle spray drier, (ii) budesonide nanocrystals and dissolved theophylline co-dispersed and processed using a 2-fluid nozzle spray drier, (iii) dissolved budesonide and dissolved theophylline processed using a 3-fluid nozzle spray drier, and (iv) budesonide nanocrystals and dissolved theophylline processed using a 3-fluid nozzle spray drier. Spray drying from the solutions resulted in co-amorphous (i) and partially amorphous powders (iii), whereas spray drying of the nanosuspensions resulted in crystalline products (ii and iv). Even though budesonide was amorphous in (i) and (iii), it failed to exhibit any dissolution advantage over the unprocessed budesonide. In contrast, the dissolution of budesonide from its nanocrystalline formulations, i.e., (ii) and (iv), was significantly higher compared to a physical mixture or unprocessed budesonide. Furthermore, the spray-dried powders obtained from the 2-fluid nozzle spray drier, i.e., (i) and (ii), exhibited co-deposition of budesonide and theophylline at the same weight ratio in the aerodynamic assessment using the New Generation Impactor. In contrast, the depositions of budesonide and theophylline deviated from the starting weight ratio in the aerodynamic assessment of spray-dried powders obtained from the 3-fluid nozzle spray drier, i.e., (iii) and (iv). Based on these results, the powders spray-dried from the suspension by using the 2-fluid nozzle spray drier, i.e., (ii), offered the best formulation properties given the physically stable crystalline solid-state properties and the co-deposition profile.

The objective of the present study is to understand the effects of drug-PEO interactions during the thermal treatment of polyethylene oxide (PEO)-based, directly compressed, abuse-deterrent formulations (ADFs). The drugs studied were dextromethorphan HBr monohydrate, ketoprofen, promethazine HCl, and anhydrous theophylline. Thermal treatment above the melting point of PEO resulted in tablets with higher crushing strength (> 500 N). It was observed that drug-PEO interactions during thermal treatment (80°C) led to solubilization of the incorporated drug. Drugs with higher solubility in the molten PEO, when added at higher weight fractions, interfered with the process of tablet densification which led to an increase in tablet dimensions and created defects in the fused matrix. These changes resulted in the formation of a more porous matrix. Thermal treatment led to a decrease in PEO crystallinity. The decreased crystallinity led to differences in the hydration and dissolution properties of the PEO. The change in dissolution properties of PEO accompanied with the dimensional and microstructural changes resulted in a greater drug release for some of the studied drugs. In conclusion, although thermal treatment above the melting point of PEO is an efficient manufacturing process in imparting crush-resistant features, drug-PEO interactions during the thermal treatment and the impact of thermal treatment on the properties of formulation components may impact tablet properties and lead to potential performance differences.

Despite extensive research in the field of gastroretentive dosage forms, this “holy grail” of oral drug delivery yet remained an unmet goal. Especially under fasting conditions, the reproducible retention of dosage forms in the stomach seems to be an impossible task. This is why such systems are often advised to be taken together with food. But also the postprandial motility can contribute significantly to the failure of gastroretentive dosage forms. To investigate the influence of postprandial pressure conditions on drug release from such systems, we used a novel in vitro dissolution tool, the dissolution stress test device. With the aid of this device, we simulated three different intragastric pressure profiles that may occur after postprandial intake. These transit scenarios were based on recently obtained, postprandial SmartPill® data. The tested systems, Glumetza® 1000 and Madopar® HBS 125, are marketed dosage forms that are based on different approaches to achieve proper gastric retention. All three transit scenarios revealed a highly pressure-sensitive drug release behavior, for both drugs. For Madopar® HBS 125, nearly complete drug release was observed even after early occurring pressures. Glumetza® 1000 seemed to be more resistant to these, most likely due to incomplete wetting of the system. On the contrary to these findings, data from standard dissolution tests using the paddle apparatus displayed controlled drug release for both systems for about 6 h. Based on these results, it can be doubted that established gastroretentive systems stay intact over a longer period of time, even under postprandial conditions.

Curcumin is the main bioactive component of Curcuma longa L. and has recently aroused growing interest from the scientific community. Unfortunately, the medicinal properties attributed to curcuminoids are impaired by their low oral bioavailability or low solubility in aqueous solutions. Many strategies have been studied to improve curcumin solubility; however, the preparation of granules using hydrophilic materials has never been attempted. The aim of this work was to develop curcumin granules by fluidized bed hot-melt granulation using the hydrophilic carrier Gelucire® 50:13. A two-level factorial design was used to verify the influence of Gelucire® 50:13 and lactose contents found in the granules on their size, morphology, bulk and tapped densities, flow, moisture content, and water activity. The granules obtained were also evaluated by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and infrared spectrometry. The curcumin solubility and dissolution rates in water were determined by liquid chromatography. The best formulation provides an increase of curcumin solubility of 4642-fold and 3.8-fold compared to the physical mixture. The dissolution tests showed a maximum drug release from granules after 45 min of 70% at pH 1.2 and 80% at pH 5.8 and 7.4, while for non-granulated curcumin, the release was below 20% in all pH. The solid-state characterization and solubility measurement showed good stability of granules over 9 months. The results attest that the fluidized bed hot-melt granulation with hydrophilic binders is an attractive and promising alternative to obtain solid forms of curcumin with enhanced bioavailability.

This review gives a brief overview about microbial contamination in pharmaceutical products. We discuss the distribution and potential sources of microorganisms in different areas, ranging from manufacturing sites, pharmacy stores, hospitals, to the post-market phase. We also discuss the factors that affect microbial contamination in popular dosage forms (e.g., tablets, sterile products, cosmetics). When these products are contaminated, the microorganisms can cause changes. The effects range from mild changes (e.g., discoloration, texture alteration) to severe effects (e.g., changes in activities, toxicity). The most common method for countering microbial contamination is the use of preservatives. We review some frequently used preservatives, and we describe the mechanisms by which microorganisms develop resistance to these preservatives. Finally, because preservatives are inherently toxic, we review the efforts of researchers to utilize water activity and other non-preservative approaches to combat microbial contamination.

Viscoelasticity is a useful parameter for characterizing the intrinsic properties of the cross-linked polyacrylate hydrogel used in cataplasm bases. The aim of this study was to investigate the effects of various formulation parameters on the rheological characteristics of polyacrylate hydrogel. The hydrogel layers were formed using a partially neutralized polyacrylate (Viscomate(™)), which contained acrylic acid and sodium acrylate in different copolymerization ratios, as the cross-linked gel framework. Dihydroxyaluminum aminoacetate (DAAA), which produces aluminum ions, was used as the cross-linking agent. Rheological analyses were performed using a "stress amplitude sweep" and a "frequency sweep". The results showed that greater amounts of acrylic acid in the structure of Viscomate as well as higher concentrations of DAAA and Viscomate led to an increase in the elastic modulus (G'). However, greater amounts of acrylic acid in the structure of Viscomate and higher concentrations of DAAA had an opposite on the viscous modulus (G″); this might be owing to higher steric hindrance. The results of this study can serve as guidelines for the optimization of formulations for cataplasms.

Biowaivers are recommended for immediate-release solid oral dosage forms using dissolution testing as a surrogate for in vivo bioequivalence studies. Several guidance are currently available (the World Health Organization (WHO), the US FDA, and the EMEA) where the conditions are described. In this study, definitions, criteria, and methodologies according to the WHO have been applied. The dissolution performances of immediate-release metronidazole, zidovudine, and amoxicillin products purchased in South African and Indian markets were compared to the relevant comparator pharmaceutical product (CPP)/reference product. The dissolution performances were studied using US Pharmacopeia (USP) apparatus 2 (paddle) set at 75 rpm in each of three dissolution media (pH1.2, 4.5, and 6.8). Concentrations of metronidazole, zidovudine, and amoxicillin in each dissolution media were determined by HPLC. Of the 11 metronidazole products tested, only 8 could be considered as very rapidly dissolving products as defined by the WHO, whereas 2 of those products could be considered as rapidly dissolving products but did not comply with the f 2 acceptance criteria in pH 6.8. All 11 zidovudine products were very rapidly dissolving, whereas in the case of the 14 amoxicillin products tested, none of those products met any of the WHO criteria. This study indicates that not all generic products containing the same biopharmaceutics classification system (BCS) I drug and in similar strength and dosage form are necessarily in vitro equivalent. Hence, there is a need for ongoing market surveillance to determine whether marketed generic products containing BCS I drugs meet the release requirements to confirm their in vitro bioequivalence to the respective reference product.

The identification of new contaminants is critical in the development of new medicinal products. Many impurities, such as pentanedioic acid, hexanedioic acid, heptanedioic acid, octanedioic acid, decanedioic acid, undecanedioic acid, dodecanedioic acid, tridecanedioic acid, and tetradecanedioic acid, have been identified in samples of azelaic acid. The aim of this study was to identify impurities observed during the stability tests of a new liposomal dosage form of azelaic acid that is composed of phosphatidylcholine and a mixture of ethyl alcohol and water, using high-performance liquid chromatography with evaporative light-scattering detector (HPLC-ELSD), gas chromatography–flame ionisation detection (GC-FID), and gas chromatography–mass spectrometry (GC-MS) methods. During the research and development of a new liposomal formulation of azelaic acid, we developed a method for determining the contamination of azelaic acid using HPLC-ELSD. During our analytical tests, we identified a previously unknown impurity of a liposomal preparation of azelaic acid that appeared in the liposomal formulation of azelaic acid during preliminary stability studies. The procedure led to the conclusion that the impurity was caused by the reaction of azelaic acid with one of the excipients that was applied in the product. The impurity was finally identified as an ethyl monoester of azelaic acid. The identification procedure of this compound was carried out in a series of experiments comparing the chromatograms that were obtained via the following chromatographic methods: HPLC-ELSD, GC-FID, and GC-MS. The final identification of the compound was carried out by GC with MS.

Formulation changes are common during drug development either due to clinical or manufacturing considerations. These changes especially at later stages of drug development oftentimes raise questions on the potential impact of a new formulation on bioavailability. In this work, the preclinical assessment of formulation bridging risk for a Biopharmaceutics Classification System II development compound is presented. Early clinical studies were conducted using a liquid-filled capsule (LFC). To assess the feasibility of a conventional solid dosage form, an initial analysis was conducted using absorption modeling which indicated conventional formulation of micronized active pharmaceutical ingredient (API) could be a viable option. Subsequently, test formulations were prepared and tested in vivo in dogs. The solid formulations were able to match exposures of the LFC capsule in the dog model; in addition, a sensitivity to API PSD was observed in line with the modeling predictions. When tested in the clinic, the conventional solid formulation resulted in exposures of approximately 25% lower compared to the LFC on an equivalent dose basis; however, bridging with a small dose adjustment would be feasible. The outcome of the clinical study was better predicted by the modeling approach while the dog model appeared to somewhat overestimate absorption. Through the use of preclinical tools and modeling and simulation, a risk assessment around formulation bridging can be conducted and inform formulation decisions or subsequent clinical study designs.

Artemisinin, a poorly water-soluble antimalarial drug, presents a low and erratic bioavailability upon oral administration. The aim of this work was to study an agglomerated powder dosage form for oral administration of artemisinin based on the artemisinin/β-cyclodextrin primary microparticles. These primary microparticles were prepared by spray-drying a water-methanol solution of artemisinin/β-cyclodextrin. β-Cyclodextrin in spray-dried microparticles increased artemisinin water apparent solubility approximately sixfold. The thermal analysis evidenced a reduction in the enthalpy value associated with drug melting, due to the decrease in drug crystallinity. The latter was also evidenced by powder X-ray diffraction analysis, while 13C-NMR analysis indicated the partial complexation with β-cyclodextrin. Agglomerates obtained by sieve vibration of spray-dried artemisinin/β-cyclodextrin primary microparticles exhibited free flowing and close packing properties compared with the non-flowing microparticulate powder. The in vitro dissolution rate determination of artemisinin from the agglomerates showed that in 10 min about 70% of drug was released from the agglomerates, whereas less than 10% of artemisinin was dissolved from raw material powder. Oral administration of agglomerates in rats yielded higher artemisinin plasma levels compared to those of pure drug. In the case of the agglomerated powder, a 3.2-fold increase in drug fraction absorbed was obtained. © 2013 American Association of Pharmaceutical Scientists.

This paper presents a novel one-step process for converting a liquid stabilized nano-suspension into a solid formulation via hot-melt extrusion combined with an internal devolatilization process (nano-extrusion, NANEX). A polymer (Soluplus®) was fed into the extruder and molten, after which a stable nano-suspension was added via side-feeding devices. The solvent (water) was removed by devolatilization and the polymer solidified at the outlet. The solid material can be tableted or filled in a capsule directly. The results showed that the obtained extrudates comprised nanocrystals in the de-aggregated form, confirming that a solid nano-formulation was prepared. This method is capable of overcoming many of the problems associated with other processes involving solid nano-dosage forms and poses a straightforward approach towards manufacturing such products.

Coating of solid dosage forms is an important unit operation in the pharmaceutical industry. In recent years, numerical simulations of drug manufacturing processes have been gaining interest as process analytical technology tools. The discrete element method (DEM) in particular is suitable to model tablet-coating processes. For the development of accurate simulations, information on the material properties of the tablets is required. In this study, the mechanical parameters Young's modulus, coefficient of restitution (CoR), and coefficients of friction (CoF) of gastrointestinal therapeutic systems (GITS) and of active-coated GITS were measured experimentally. The dynamic angle of repose of these tablets in a drum coater was investigated to revise the CoF. The resulting values were used as input data in DEM simulations to compare simulation and experiment. A mean value of Young's modulus of 31.9 MPa was determined by the uniaxial compression test. The CoR was found to be 0.78. For both tablet-steel and tablet-tablet friction, active-coated GITS showed a higher CoF compared with GITS. According to the values of the dynamic angle of repose, the CoF was adjusted to obtain consistent tablet motion in the simulation and in the experiment. On the basis of this experimental characterization, mechanical parameters are integrated into DEM simulation programs to perform numerical analysis of coating processes.

The controlled release of diflunisal and fluconazole from tablets made of novel polymers, poly(acrylic acid) (PAA) crosslinked with either β-cyclodextrin (βCD) or hydroxypropyl-βCD (HPβCD), was investigated and Carbopol 934P (Carbopol) was used as a highly crosslinked PAA for comparison. Diflunisal strongly associates with βCD-PAA and HPβCD-PAA polymers (Ka of 486 and 6,055 M(-1) respectively); thus, it was physically mixed into the conjugates and also precomplexed to identify whether decomplexation has any influence on release kinetics. Fluconazole has poor complexing ability (Ka of 34 M(-1) with HPβCD-PAA); thus, it was only tested as a physical mixture. Swelling and adhesion studies were conducted on all tablet combinations and adhesivity of the CD-PAA polymer tablets was maintained. Diflunisal release was much slower from HPβCD-PAA tablets than from βCD-PAA, suggesting that a higher degree of complexation retards release. The precomplexed diflunisal release was also slower than the physically mixed diflunisal of the corresponding conjugate. The release closely followed zero-order kinetics for HPβCD-PAA, but was more sigmoidal for βCD-PAA and especially Carbopol. Conversely, poorly associating fluconazole released in almost exactly the same way across both polymers and Carbopol, indicating that the release kinetics of poorly associating drugs are not influenced by the presence of cyclodextrins. In view of the varying profiles and release rates shown with diflunisal for the different polymers, the fluconazole data support the concept that adequate complexation can indeed modulate the release kinetics of drugs.

To ensure optimal, reliable treatment, it is necessary to investigate the efficacy, safety and the optimal dose of drug substances and to develop suitable age-specific pharmaceutical formulations for the different paediatric age groups due to a lack of evidence-based therapeutic options for children. While WHO recommends the use of solid dosage forms in general, European Medicines Agency (EMA) requires evidence for the suitability of these dosage forms in the targeted age group. This review aims to summarize and discuss the data obtained in acceptability studies on the suitability of coated and uncoated mini-tablets in children of different ages in comparison to a sweet syrup considered as gold standard. The predefined outcome parameters 'acceptability' and 'capability to swallow' of the two different mini-tablet formulations (uncoated and film-coated) were statistically significantly higher than that of the syrup.

In Europe, the development of pediatric medicines for new patent protected products is mandatory and applicants are required to submit a Paediatric Investigation Plan (PIP) to the regulatory authorities. The process is voluntary for off-patent medicines and despite the availability of incentives, there is still a huge unmet need for the development of off-patent pediatric medicines. The aim of the EU grant funded "Labeling of Enalapril from Neonates to Adolescents" (LENA) project is to develop a new pediatric dosage form of the off-patent drug enalapril, for the treatment of heart failure in patients aged from birth to 18 years. This article provides an overview of some of the key formulation challenges that were faced during the product development programme and PIP process, including selection of dosage form and excipients, methodology for administration of the product and evaluation of patient acceptability.

The dissolution of several products containing Biopharmaceutical Classification System (BCS) class III drugs, acyclovir, atenolol, and ciprofloxacin hydrochloride, listed in the WHO essential drug list (EDL), was tested and compared with their respective comparator pharmaceutical products (CPPs) marketed in South Africa and India. US Pharmacopeia (USP) buffers of pH 1.2, 4.5, and 6.8 were used as dissolution media and tested using USP apparatus 2 at 75 rpm and 900 ml. Nine acyclovir products were tested, and only three dissolved very rapidly in all media; i.e., they showed a release of >85% in 15 min. Eight atenolol products tested were all very rapidly dissolving in all three pH media. Ten ciprofloxacin hydrochloride products were tested, and the results showed that only five products met the WHO biowaiver criteria. This study indicates that not all marketed products containing the same BCS III active pharmaceutical ingredient (API) in similar strength and dosage form are necessarily in vitro equivalent as per the WHO biowaiver criteria. Furthermore, selection and availability of an innovator product as CPP are important considerations that can affect the outcomes of such studies.

In the current study, the potential of a novel combination of a galactomannan with acarbose (100 mg) was evaluated for attaining a desired hypoglycaemic effect over a prolonged period of time. Three major antidiabetic galactomannans viz., fenugreek gum, boswellia gum, and locust bean gum were selected in order to achieve a synergistic effect in the treatment alongwith retardation in drug release. In vitro studies indicated that batches containing various proportions of fenugreek gum (AF40-60) were able to control drug release for a longer duration of approximately 10–12 h. In contrast, the matrices prepared using boswellia and locust bean gum were able to sustain the release for relatively shorter durations. Drug release mainly followed first-order release kinetics owing to the highly soluble nature of the drug. In vivo study depicted a significant reduction (p