Properties Of Dosage Forms Research Articles

Method and technology for drug repurposing based on changes in the physicochemical properties of dosage forms: experience of use in Russia

Controlled local hyperthermia and hypothermia are important factors in drug pharmacodynamics and pharmacokinetics because changing the temperature of drugs changes their physicochemical properties. In this regard, a controlled change in the temperature of the drug and/or the body part with which the drug interacts, relative to the level of human body temperature (hyperthermia or hypothermia) forms the basis of temperature pharmacology. To analyze the authors publications on the problem of methodology and technology for repurposing drugs based on changes in the physicochemical properties of dosage forms. A controlled change in the temperature of the drug and/or the part of the body with which the drug interacts; a change in acid (alkaline), osmotic activity, and the degree and quality of carbonation and/or oxygen-forming activity of medicinal solutions; and a change in the concentration of medicinal solution ingredients. On the basis of the used methods, the reprofiling of a number of drugs has been achieved. The author proposed reprofiling a 4% potassium chloride solution from the group of macroelements and microelements used to regulate acid-base balance with a resorptive effect (when administered intravenously to the whole body) into a group of vasoconstrictive drugs used to stop bleeding when applied to by a single irrigation of the bleeding surface. Cooling certain drugs and tissues at their interaction sites to 18C20C (via an ice pack or its substitute) inhibits metabolism and function, ensuring the conversion of many drugs into anti-ischemic drugs by reducing the need for tissues in oxygen. A targeted change in the physicochemical properties of known drugs combined with local hyperthermia allows them to be converted into expectorant, pyrolytic (astringent), hemolytic, thrombolytic (hemostatic), detergent, bleaching, cleaning, and other drugs, including antiseptic and cauterizing (necrotizing) drugs, very reliably, quickly, and inexpensively. Thus, 40 years ago, pharmacologists of the Russian Federation established the foundation for a novel method of drug development known today as repurposing of existing drugs. Today, it is evident that reprofiling may rapidly, inexpensively, and effectively give existing drugs a new purpose.

Kinetic Modeling to Explain the Release of Medicine from Drug Delivery Systems

AbstractProper medication dissolution must be ensured when developing or manufacturing a new solid dosage form. Quantitative analyses performed in dissolution or release tests become simpler when applying mathematical formulae which represent dissolution outcomes as a function of several dosage form properties. Methodologies utilized to examine the kinetics of drug release from controlled‐release formulations are reviewed. The analysis of variance was conducted using statistical, model‐independent, and ‐dependent techniques for the dissolution profile comparison and fitting, respectively. Model equations, including zero‐ and first‐order, Hixson‐Crowell, Weibull, Higuchi, Korsmeyer‐Peppas, Baker‐Lonsdale, Hopfenberg, etc., were employed to match the experimental data. Additional release parameters were taken to illustrate the drug release patterns. Using correlation factors and the Akaike information criterion (AIC), the best‐fitting model was discovered, as were the transport phenomena affecting the behavior of the recognized formulations.

Navigating the complexities of medicating paediatric patients: Insights from an enteral feeding tube workshop

Enteral feeding tubes (EFT) are used to administer nutrition into the gastrointestinal tract of patients who are unable to take nutrition via mouth. A wide range of children may require enteral feeding through EFT which are also used to administer medication. However, many medicines are not licensed for administration via this route. Numerous factors can impact EFT medicine administration, including for example, dosage form properties and composition, EFT size, design and material, and operational aspects such as tube flushing. As a result, the risk of sub-optimal dosing and medication error is much higher in patients with EFT compared to those without. EuPFI organised a preconference workshop to review the current state of knowledge around aspects to be considered in the verification of EFT administration of medications to children, and considerations for EFT use, and to highlight the areas that remain challenging. Healthcare professional, pharmaceutical industry and regulatory agency perspectives were shared, and case studies discussed. It was agreed that simple and clear standardised global procedures are required for the evaluation and administration of medicines via EFT, and collaboration between all key stakeholders is recommended.

Impact of polymer chemistry on critical quality attributes of selective laser sintering 3D printed solid oral dosage forms

The aim of this study is to investigate the influence of polymer chemistry on the properties of oral dosage forms produced using selective laser sintering (SLS). The dosage forms were printed using different grades of polyvinyl alcohol or copovidone in combination with indomethacin as the active pharmaceutical ingredient. The properties of the printed structures were assessed according to European Pharmacopoeia guidelines at different printing temperatures and laser scanning speeds in order to determine the suitable printing parameters.The results of the study indicate that the chemical properties of the polymers, such as dynamic viscosity, degree of hydrolyzation, and molecular weight, have significant impact on drug release and kinetics. Drug release rate and supersaturation can be modulated by selecting the appropriate polymer type. Furthermore, the physical properties of the dosage forms printed under the same settings are influenced by the selected polymer type, which determines the ideal manufacturing settings.This study demonstrates how the chemical properties of the polymer can determine the appropriate choice of manufacturing settings and the final properties of oral dosage forms produced using SLS.

Development of New Generation Drugs by Enriching Them with Gases

Until today, the mechanism of action of drugs is traditionally considered without taking into account the physical-chemical properties of dosage forms. However, at the beginning of the 21st century, there were reports that all drugs contain unaccounted gases that enter drugs from the air and affect the quality of drugs. It is shown that the composition and amount of gases in the dosage forms of all drugs changes their mechanical, physical, chemical and physical-chemical properties and the mechanism of action of drugs, especially when applied topically It is reported that changing the content of gases in drug solutions and tablets allows to regulate their mass, volume, specific gravity, porosity, physico-chemical activity and local action on the routes of drug administration. The identification of this pattern allowed to start the production of completely new drugs with a certain gas composition and with a new local pharmacokinetics and a new local pharmacodynamics. The formulations of new drugs in which gas is an auxiliary, formative or main ingredient are given. It is proposed to control the gas composition of medicines as an indicator of their quality and an important factor of their physical-chemical activity. It is proved that the gas in the drug can be not only neutral, but also auxiliary, oppositional, and sometimes the main ingredient. Thus, the control and accounting of the gas contained in drugs will allow the creation of a new generation of drugs in the near future.

Selective laser sintering additive manufacturing of dosage forms: Effect of powder formulation and process parameters on the physical properties of printed tablets

Large batches of placebo and drug-loaded solid dosage forms were successfully fabricated using selective laser sintering (SLS) 3D printing in this study. The tablet batches were prepared using either copovidone (N-vinyl-2-pyrrolidone and vinyl acetate, PVP/VA) or polyvinyl alcohol (PVA) and activated carbon (AC) as radiation absorbent, which was added to improve the sintering of the polymer. The physical properties of the dosage forms were evaluated at different pigment concentrations (i.e., 0.5 and 1.0 wt%) and at different laser energy inputs. The mass, hardness, and friability of the tablets were found to be tunable and structures with greater mass and mechanical strength were obtained with increasing carbon concentration and energy input. Amorphization of the active pharmaceutical ingredient in the drug-loaded batches, containing 10 wt% naproxen and 1 wt% AC, was achieved in-situ during printing. Thus, amorphous solid dispersions were prepared in a single-step process and produced tablets with mass losses below 1 wt%. These findings show how the properties of dosage forms can be tuned by careful selection of the process parameters and the powder formulation. SLS 3D printing can therefore be considered to be an interesting and promising technique for the fabrication of personalized medicines.

Dataset on a Small-Scale Film-Coating Process Developed for Self-Expanding 4D Printed Drug Delivery Devices

Film-coating is widely applied in pharmaceutics to enhance aspect/taste and mechanical properties of dosage forms, to protect them from the environment and to modify their release performance. In this respect, a film-coating process was recently involved in the development of 4D printed prolonged-release systems intended for organ retention. During coating processes, liquid formulations are sprayed onto moving cores, whose shape, weight and surface characteristics are essential to attain a homogeneous film. Devices of complex shapes, composed of smart materials and fabricated by hot-processing techniques, such as extrusion and fused deposition modeling 3D printing, might be poorly compatible with the requirements of traditional coating methods, e.g., need for spherical substrates with smooth surface and stable under process temperatures. This work was aimed at evaluating, at a small scale level, the feasibility of a versatile equipment for film-coating of rod-shaped extruded and printed prototypes with different section. Equipment design and set up of process parameters were performed starting from polymeric solutions and suspensions and selecting as cores 50 mm-long rod-shaped samples based on shape memory poly(vinyl alcohol). Integrity and thickness of the applied layer and its impact on shape memory and release performance of prototypes were investigated.

Recent Advances in 3D Printing for Parenteral Applications.

3D printing has emerged as an advanced manufacturing technology in the field of pharmaceutical sciences. Despite much focus on enteral applications, there has been a lack of research focused on potential benefits of 3D printing for parenteral applications such as wound dressings, biomedical devices, and regenerative medicines. 3D printing technologies, including fused deposition modeling, vat polymerization, and powder bed printing, allow for rapid prototyping of personalized medications, capable of producing dosage forms with flexible dimensions based on patient anatomy as well as dosage form properties such as porosity. Considerations such as printing properties and material selection play a key role in determining overall printability of the constructs. These parameters also impact drug release kinetics, and mechanical properties of final printed constructs, which play a role in modulating immune response upon insertion in the body. Despite challenges in sterilization of printed constructs, additional post-printing processing procedures, and lack of regulatory guidance, 3D printing will continue to evolve to meet the needs of developing effective, personalized medicines for parenteral applications.

Multivariate analysis in the development of bioequivalent tablets containing bicalutamide

The pharmaceutical industry has to tackle the explosion of high amounts of poorly soluble APIs. This phenomenon leads to numerous sophisticated solutions. These include the use of multifactorial data analysis identifying correlations between the components and dosage form properties, laboratory and production process parameters with respect to the API liberation Example of such API is bicalutamide. Improved liberation is achieved by particle size reduction. Laboratory batches, with different PSD of API, were filled into gelatinous capsules and consequently granulated for tablet compression. Comparative dissolution profiles with Casodex 150 mg (Astra Zeneca) were performed. The component analysis was used for the statistical evaluation of f1 and f2 factors and D(v,0.9) and D[4,3] parameters of PSD to identify optimal PSD values. Suitable PSD limits for API were statistically confirmed in laboratory and in commercial scale with respect to optimized tablet properties. The tablets were bioequivalent with originator (n = 20; 90% CI for ln AUC0–120: 99.8–111.9%; 90% CI for ln cmax: 101.1–112.9%). In conclusion, the micronisation of the API is still an efficient and inexpensive method improving the bioavailability, although there are more complicated and expensive methods available. Statistical multifactorial methods improved the safety and reproducibility of production.

Effects of granulation process variables on the physical properties of dosage forms by combination of experimental design and principal component analysis

The current study was to understand how process variables of high shear wet granulations affect physical properties of granules and tablets. The knowledge gained was intended to be used for Quality-by-Design based process design and optimization. The variables were selected based on the risk assessment as impeller speed, liquid addition rate, and wet massing time. Formulation compositions were kept constant to minimize their influence on granules properties. Multiple linear regression models were built providing understanding of the impact of each variable on granule hardness, Carr's index, tablet tensile strength, surface mean diameter of granules, and compression behavior. The experimental results showed that the impact of impeller speed was more dominant compared to wet massing time and water addition rate. The results also revealed that quality of granules and tablets could be optimized by adjusting specific process variables (impeller speed 1193 rpm, water spray rate 3.7 ml/min, and wet massing time 2.84 min). Overall desirability was 0.84 suggesting that the response values were closer to the target one. The SEM image of granules showed that spherical and smooth granules produced at higher impeller speed, whereas rough and irregular shape granules at lower speed. Moreover, multivariate data analysis demonstrated that impeller speed and massing time had strong correlation with the granule and tablet properties. In overall, the combined experimental design and principal component analysis approach allowed to better understand the correlation between process variables and granules and tablet attributes.

Quantifying Disproportionation in Pharmaceutical Formulations with 35Cl Solid-State NMR.

Reliable methods for the characterization of drug substances are critical for evaluating stability and bioavailability, especially in dosage formulations under varying storage conditions and usage. Such methods must also give information on the molecular identities and structures of drug substances and any potential byproducts of the formulation process, as well as providing a means of quantifying the relative amounts of these substances. For example, active pharmaceutical ingredients (APIs) are often formulated as ionic salts to improve the pharmaceutical properties of dosage forms; however, exposure of such formulations to elevated temperature and/or humidity can trigger the conversion of an ionic salt of an API to a neutral form with different properties, through a process known as disproportionation. It is particularly challenging to identify changes of pharmaceutical components in solid dosage formulations, which are complex heterogeneous mixtures of the API and excipient components (e.g., binders, disintegrants, and lubricants). In this study, we illustrate that ultra-wideline (UW) 35Cl solid-state NMR (SSNMR) can be used to characterize the disproportionation reaction of pioglitazone HCl (PiogHCl) in mixtures with metallic stearate excipients. 35Cl SSNMR can quantitatively detect the amount of PiogHCl in mixed samples within ±1 wt % and measure the degree of PiogHCl disproportionation in formulation samples stressed at high relative humidity and temperature. Unlike other methods used for characterizing disproportionation, our experiments directly probe the Cl- anions in both the intact salt and disproportionation products, revealing all of the chlorine-containing products in the solid-state chemical reaction without interfering signals from the formulation excipients.

Development of Itraconazole Tablets Containing Viscous KinetiSol Solid Dispersions: In Vitro and In Vivo Analysis in Dogs.

The formulation factors relevant to developing immediate and controlled release dosage forms containing poorly soluble drugs dispersed in amorphous systems are poorly understood. While the utility of amorphous solid dispersions is becoming apparent in the pharmaceutical marketplace, literature reports tend to concentrate on the development of solid dispersion particulates, which then must be formulated into a tablet. Amorphous solid dispersions of itraconazole in high molecular weight hydroxypropyl methylcellulose were prepared by KinetiSol® Dispersing and tablets were formulated to immediately disintegrate or control the release of itraconazole. Formulated tablets were evaluated by two non-sink dissolution methodologies and the dosage form properties that controlled the gelling tendency of the dispersion carrier, hydroxypropyl methylcellulose, were investigated. Selected formulations were evaluated in an exploratory beagle dog pharmacokinetic study; the results of which indicate potential for a prolonged absorption phase relative to the commercially extruded control.

3D-micro-patterned fibrous dosage forms for immediate drug release

At present, the most prevalent pharmaceutical dosage forms, the orally-delivered immediate-release tablets and capsules, are porous, granular solids. They disintegrate into their constituent particulates upon ingestion to release drug rapidly. The design, development, and manufacture of such granular solids, however, is inefficient due to difficulties associated with the unpredictable inter-particle interactions. Therefore, to achieve more predictable dosage form properties and processing, we have recently introduced melt-processed polymeric cellular dosage forms. The cellular forms disintegrated and released drug rapidly if the cells were predominantly interconnected. Preparation of interconnected cells, however, relies on the coalescence of gas bubbles in the melt, which is unpredictable. In the present work, therefore, new melt-processed fibrous dosage forms with contiguous void space are presented. The dosage forms are prepared by melt extrusion of the drug-excipient mixture followed by patterning the fibrous extrudate on a moving surface. It is demonstrated that the resulting fibrous structures are fully predictable by the extruder nozzle diameter and the motion of the surface. Furthermore, drug release experiments show that the disintegration time of the fibrous forms prepared in this work is of the order of that of the corresponding single fibers. The thin fibers of polyethylene glycol (excipient) and acetaminophen (drug) in turn disintegrate in a time proportional to the fiber radius and well within immediate-release specification. Finally, models of dosage form disintegration and drug release by single fibers and fibrous dosage forms are developed. It is found that drug release from fibrous forms is predictable by the physico-chemical properties of the excipient and such microstructural parameters as the fiber radius, the inter-fiber spacing, and the volume fraction of water-soluble excipient in the fibers.

The Role of Solid State Characterization in Predicting Stability of Solid Dosage Forms.

Stability of a dosage form is its ability to preserve its quality attributes within preset limits. The time span over which these attributes remain within specifications is the shelf-life of the drug product. Stability is a very complex feature and is influenced not only by the stability of the drug substance but also by the stability of excipients and the interaction of the components within the system. Another important contributing factor is the packaging material, which is responsible for the protection of the drug product. Not only drug substances, but also excipients are susceptible to different degradation mechanisms. Amorphous polymers, a relatively frequently used group of excipients, are especially prone to physical instability. Through the process of physical ageing, a slow volume and enthalpy relaxation can be experienced, which can lead to remarkable alterations in solid dosage form properties. Functional changes within the solid dosage form associated with instability include changes in mechanical properties, homogeneity and drug release characteristics, discoloration, phase separation or changes in melting time of suppositories. Stability assessment is a crucial issue during formulation development, which is strictly regulated by authorities responsible for drug registration. The primary purpose of this paper is to give an overview of the different types of physical changes influencing solid state stability of dosage forms, and how such changes can be monitored. We will also illustrate how the quality of a solid dosage form varies with time under the influence of different environmental factors.

Microparticle surface layering through dry coating: impact of moisture content and process parameters on the properties of orally disintegrating tablets.

The aim of this study was to investigate the influence of process parameters during dry coating on particle and dosage form properties upon varying the surface adsorbed moisture of microcrystalline cellulose (MCC), a model filler/binder for orally disintegrating tablets (ODTs). The moisture content of MCC was optimised using the spray water method and analysed using thermogravimetric analysis. Microproperty/macroproperty assessment was investigated using atomic force microscopy, nano-indentation, scanning electron microscopy, tablet hardness and disintegration testing. The results showed that MCC demonstrated its best flowability at a moisture content of 11.2% w/w when compared to control, comprising of 3.9% w/w moisture. The use of the composite powder coating process (without air) resulted in up to 80% increase in tablet hardness, when compared to the control. The study also demonstrated that surface adsorbed moisture can be displaced upon addition of excipients during dry processing circumventing the need for particle drying before tabletting. It was concluded that MCC with a moisture content of 11% w/w provides a good balance between powder flowability and favourable ODT characteristics.

Significance of Pharmaceutical Excipients on Solid Dosage form Development: A Brief Review

The rapid and vibrant growth of pharmaceutical industries leads to newer challenges in field of formulation development. With the launch of new Active Pharmaceutical Ingredients and also the excipient possessing different physicochemical properties, it is really a challenging task for a formulation scientist in presenting a viable, suitable and stable dosage formulation. Many failures in pharmaceutical formulation manufacturing processes are caused due to issues related to Pharmaceutical excipients. Selection of wrong excipient not only affects the physicochemical properties of dosage form but also affect the biopharmaceutical characters. Along with drug excipient incompatibilities, improper ratio of excipients, particle characters including molecular and bulk characters of excipients affect the dosage form characters. Thus in current review, the significance of various properties of excipient on the physicochemical and biological behavior of dosage form and the criteria for selection of excipients in designing of robust formulation is summarized. Disintegrating agents and lubricating agents are the excipients, although required in very small proportion, but their physicochemical characters and ratio in formulation highly affects the formulation properties. Thus, in current review special emphasis is given on the effect of disintegrating agents and lubricating agents on the characteristics of tablet dosage form.

PATH FINDER PROCESS VALIDATION OF MOIST HEAT STERILIZER IN PARENTRAL MANUFACTURING UNIT

Objective:- Moist heat sterilization is the most important in pharmaceutical Parentral manufacturing unit. Sterile products have several unique dosage form properties, such as freedom from microorganisms, freedom from pyrogens, freedom from particulates, and extremely high standards of purity and quality; however, the ultimate goal in the manufacture of a sterile product is absolute absence of microbial contamination. An attempt has been made in this research work to validate the Moist Heat Steriliser with technical parameters  classified as Critical and Variable Parameters. Method:- Moist Heat Sterilization method is used for Sterilization of Accessories,Garments ,Silicon tubes, filtration assembly etc. on basis of coagulation of cell proteins. Moist Heat Steriliser  is validated every half year to ensure the system is liable to consistently, provide dehydrogenated or sterile product and meets the quality standards. Validation is done by proper planning by taking regular load and experimental load of regular batches of the product. The study is done on Heat distribution, Heat penetration, and Bio burden determination, Minimize the utility cost, and Man hours during sterilization cycle. Result:- The result found in this research work leads to setting up New approach to Validate Moist Heat Steriliser in Parentral manufacturing unit with cost effective way. Conclusion:- The Path finder validation process setup through this project is Cost saving through Energy as well as Man Hour Saving and Breakage of Units also maintain Sterility in product. It is helpful to find out Hot and Cold Spots in Moist Heat sterilizer and Designing and   Placement of RTDs. The findings were submitted to the Parentral Department of Vital HealthCare Pvt. Ltd., Satpur. MIDC, Nashik. KEYWORDS:-Moist heat Sterilization , Process Validation , Critical and Variable parameters.

Understanding pharmaceutical polymorphic transformations II: crystallization variables and influence on dosage forms.

Excipients or formulation variables have often been exploited to improve stability, modify release, or improve physicochemical properties of dosage forms. In pharmaceutical field, it is generally expected that excipients work at macromolecular level where they might influence the crystal structure of a solid. These polymers/colloidal particles may modify the rate and direction of crystal growth. It has also been observed, that different polymorphic crystals exhibit different colors on exposure to same colorant, predominantly due to difference in surface pH of different crystal lattices. Apart from physicochemical affect, crystal habit also influences pharmacokinetic parameters of the dosage form. Crystals with smaller size or lower lattice energy have shown to exhibit higher bioavailability with faster rate of release.

Application of physical methods of pharmacy to improve the properties of dosage forms

It has been shown on the examples of paracetamol, ibuprofen, and salbutamol that the use of mixed water-organic solvents, which are capable of clathrate formation, enables one to obtain high-disperse drug powders that are weakly soluble in water via sublimation drying of frozen solutions. The prepared powders are applicable for direct compression to pellets, have a higher rate of passing into solution for drug compared to initial substances, and can be used to prepare the suspensions for children’s preparations and dosage forms as freon-free aerosols for pulmonary administration.

Application of the Dynamic Gastric Model to evaluate the effect of food on the drug release characteristics of a hydrophilic matrix formulation

Characterisation of the effect of food on the bio-performance of modified and extended release dosage forms can be very challenging due to the need to replicate the dynamic biochemical conditions of the human gut as well as the complex physical processing modalities under fed state. Classical compendial methods are useful for testing the quality of pharmaceutical dosage forms but typically have limitations in the accurate prediction of food-effect in-vivo. Preliminary evaluation of the Dynamic Gastric Model (DGM) shows that it can provide substantially more detailed mechanistic information on dosage form properties compared to conventional compendial testing. The potential effect of food on the drug release and physical properties of a hydrophilic matrix formulation containing a model drug, hydrochlorothiazide, was studied using compendial methods, bio-relevant media and the DGM (in combination with an off-line intestinal model). Whilst the compendial methods with biorelevant media provided good correlation with the dissolution rates observed using the DGM/intestinal model under simulated fasted state, the quantification of simulated fed state performance changes was much more challenging using the compendial methods. Classical compendial studies using biorelevant FeSSIF and FaSSIF media could not readily discern differences in dissolution performance under fasted and fed states; however, the DGM could detect significant changes in both physical properties as well as drug release performance under fed state processing.