Orodispersible films – characteristics of quality assessment methods

Orodispersible films (ODF) are defined in the European Pharmacopoeia as “single or multilayered sheets of suitable materials, to be placed in the mouth where they disperse rapidly”. They are indicated as an appropriate form of medicine for pediatric and geriatric patients suffering from mental disorders, as well as bedridden or uncooperative patients. ODFs should be characterized by good mechanical properties and short disintegration time, as well as appropriate pharmaceutical availability of the active pharmaceutical ingredient (API). In addition, they should have a smooth surface, as well as appropriate taste and texture that do not cause an unpleasant sensation in the mouth. For this reason, during research and development, special attention is paid to disintegration time, mechanical properties, size, texture, mouthfeel after application and disintegration, as well as taste. Due to the lack of pharmacopoeial guidelines on how to assess the quality of ODF films, different standards and tests proposed in the literature are used. The disintegration time of the ODFs is indicated as key factor affecting patients’ acceptability of this dosage form. So far, many in vivo methods have been developed to assess this parameter. Among them, commonly methods, i.e. a Petri dish, a slide frame, a slide frame and ball, a pharmacopoeial apparatus, as well as novel methods, i.e. using a model of the oral cavity and a tribometer are utilized. Ensuring appropriate mechanical properties of ODFs are crucial during developing this dosage form. According to the pharmacopoeial definition, the ODFs should “possess suitable mechanical strength to resist handling without being damaged”. In order to assess the mechanical properties of ODF films, tensile strength, puncture test and tear resistance tests are carried out. The aim of this study is to present and characterized the research methods which are applied to assess the quality of ODFs, with particular emphasis on methods used for disintegration time and mechanical properties assessing

Preformulation studies on solid self-emulsifying systems in powder form containing magnesium aluminometasilicate as porous carrier

The influence of alkaline and the neutral grade of magnesium aluminometasilicate as a porous solid carrier for the liquid self-emulsifying formulation with ibuprofen is investigated. Ibuprofen is dissolved in Labrasol, then this solution is adsorbed on the silicates. The drug to the silicate ratio is 1:2, 1:4, and 1:6, respectively. The properties of formulations obtained are analyzed, using morphological, porosity, crystallinity, and dissolution studies. Three solid self-emulsifying (S-SE) formulations containing Neusilin SG2 and six consisting of Neusilin US2 are in the form of powder without agglomerates. The nitrogen adsorption method shows that the solid carriers are mesoporous but they differ in a specific surface area, pore area, and the volume of pores. The adsorption of liquid SE formulation on solid silicate particles results in a decrease in their porosity. If the neutral grade of magnesium aluminometasilicate is used, the smallest pores, below 10 nm, are completely filled with liquid formulation, but there is still a certain number of pores of 40–100 nm. Dissolution studies of liquid SEDDS carried out in pH = 1.2 show that Labrasol improves the dissolution of ibuprofen as compared to the pure drug. Ibuprofen dissolution from liquid SE formulations examined in pH of 7.2 is immediate. The adsorption of the liquid onto the particles of the silicate causes a decrease in the amount of the drug released. Finally, more ibuprofen is dissolved from S-SE that consist of the neutral grade of magnesium aluminometasilicate than from the formulations containing the alkaline silicate

Prescription drug forms with midazolam.

Midazolam jest pochodną benzodiazepiny, o krótkim biologicznym okresie półtrwania, stosowanym w pediatrii do sedacji przed znieczuleniem oraz w stomatologii. Dostępny jest w postaci tabletek oraz preparatów do wstrzykiwań. W terapii pediatrycznej zalecane jest podanie płynnej doustnej postaci leku, z uwagi na trudności w połykaniu tabletek. Ze względu na brak substancji pro receptura proponowane jest sporządzanie leku recepturowego z preparatu do wstrzykiwań z zastosowaniem m.in. syropu prostego, bazy Syrspend® SF pH 4, HPMC jako substancji pomocniczych.Midazolam is a benzodiazepine derivative. It is characterized by a short half-life. It has a strong sedative, anxiolytic and hypnotic effect. It also acts as an anticonvulsant and relaxes skeletal muscles. Due to the short half-life and quick onset of action it is used in pediatrics for sedation before anesthesia and in dentistry. The literature provides indications for midazolam in the range of 0.2 to 1 mg/kg body weight. In pediatric therapy, the oral dose should not be higher than 0.75 mg/kg. When a dose of 0.25 mg/kg is used, the risk of side effects is low, while when the maximum dose is exceeded, respiratory depression and respiratory arrest may occur. Midazolam is metabolized by the cytochrome P450 3A4 in the intestines and the liver. Inhibition of the activity of CYP450 3A4, e.g. by grapefruit juice, causes a reduced absorption of the drug in the intestines and its delayed action, as well as a reduction in the first-pass effect, which increases the concentration of midazolam in the blood. Midazolam is a weak acid with a pKa of 6,2 in water. At physiological pH midazolam is an active form, hydrophobic drug, having a weak solubility in water. Due to its lipophilic nature, it is quickly absorbed from the gastrointestinal tract and penetrates the central nervous system. It has a short effect. Injection solutions contain midazolam as hydrochloride. The solubility of midazolam hydrochloride is pH dependent and increases with decreasing value. The stability of midazolam in the pH range from 3 to 3.6 was determined. Midazolam can be administered: parenterally, orally, rectally, sublingually, nasally, and also by inhalation. There were no significant differences in bioavailability by route of administration. It is available as injection and tablets. The oral liquid form is recommended for children because of the difficulty in swallowing tablets. In absence of commercially prepared midazolam syrup Versed® or oral solution Ozalin® in some countries, injection formulation of midazolam are used for oral administration. Intravenous formulation exhibit strong bitter taste, in order to improve the acceptance by children Syrup BP, Syrspend® SF pH 4, Ora-Sweet®, citrus juices except grapefruit juice, HPMC are proposed as excipients to prepare a prescription drug forms from injection

Magnetic resonance imaging analysis of moving fronts in floating dosage forms

An application of magnetic resonance imaging in the field of pharmaceutical technology is presented in this paper. The analysis of diffusion and swelling fronts was carried out for four floating dosage forms using magnetic resonance imaging. The influence of polymer viscosity, its concentration, and type of applied dissolution media on the area of moving fronts was investigated

Generalized in vitro-in vivo relationship (IVIVR) model based on artificial neural networks

Background: The aim of this study was to develop a generalized in vitro-in vivo relationship (IVIVR) model based on in vitro dissolution profiles together with quantitative and qualitative composition of dosage formulations as covariates. Such a model would be of substantial aid in the early stages of development of a pharmaceutical formulation, when no in vivo results are yet available and it is impossible to create a classical in vitro-in vivo correlation (IVIVC)/IVIVR. Methods: Chemoinformatics software was used to compute the molecular descriptors of drug substances (ie, active pharmaceutical ingredients) and excipients. The data were collected from the literature. Artificial neural networks were used as the modeling tool. The training process was carried out using the 10-fold cross-validation technique. Results: The database contained 93 formulations with 307 inputs initially, and was later limited to 28 in a course of sensitivity analysis. The four best models were introduced into the artificial neural network ensemble. Complete in vivo profiles were predicted accurately for 37.6% of the formulations. Conclusion: It has been shown that artificial neural networks can be an effective predictive tool for constructing IVIVR in an integrated generalized model for various formulations. Because IVIVC/IVIVR is classically conducted for 2–4 formulations and with a single active pharmaceutical ingredient, the approach described here is unique in that it incorporates various active pharmaceutical ingredients and dosage forms into a single model. Thus, preliminary IVIVC/IVIVR can be available without in vivo data, which is impossible using current IVIVC/IVIVR procedures

Optimization of furosemide liquisolid tablets preparation process leading to their mass and size reduction

The great number of drug substances currently used in solid oral dosage forms is characterized by poor water solubility. Therefore, various methods of dissolution rate enhancement are an important topic of research interest in modern drug technology. The purpose of this study was to enhance the furosemide dissolution rate from liquisolid tablets while maintaining an acceptable size and mass. Two types of dibasic calcium phosphate (FujicalinÆ/EmcompressÆ) and microcrystalline cellulose (VivapurÆ 102/VivapurÆ 12) were used as carriers and magnesium aluminometasilicate (NeusilinÆ US2) was used as a coating material. The flowable liquid retention potential for those excipients was tested by measuring the angle of slide. To evaluate the impact of used excipients on tablet properties fourteen tablet formulations were prepared. It was found that LS2 tablets containing spherically granulated dibasic calcium phosphate and magnesium aluminometasilicate exhibit the best dissolution profile and mechanical properties while tablets composed only with NeusilinÆ US2 was characterized by the smallest size and mass with preserved good mechanical properties and furosemide dissolution

Printing techniques : recent developments in pharmaceutical technology

In the last few years there has been a huge progress in a development of printing techniques and their application in pharmaceutical sciences and particularly in the pharmaceutical technology. The variety of printing methods makes it necessary to systemize them, explain the principles of operation, and specify the possibilities of their use in pharmaceutical technology. This paper aims to review the printing techniques used in a drug development process. The growing interest in 2D and 3D printing methods results in continuously increasing number of scientific papers. Introduction of the first printed drug SpritamÆ to the market seems to be a milestone of the 3D printing development. Thus, a particular aim of this review is to show the latest achievements of the researchers in the field of the printing medicines

Empirical modeling of the fine particle fraction for carrier-based pulmonary delivery formulations

In vitro study of the deposition of drug particles is commonly used during development of formulations for pulmonary delivery. The assay is demanding, complex, and depends on: properties of the drug and carrier particles, including size, surface characteristics, and shape; interactions between the drug and carrier particles and assay conditions, including flow rate, type of inhaler, and impactor. The aerodynamic properties of an aerosol are measured in vitro using impactors and in most cases are presented as the fine particle fraction, which is a mass percentage of drug particles with an aerodynamic diameter below 5 µm. In the present study, a model in the form of a mathematical equation was developed for prediction of the fine particle fraction. The feature selection was performed using the R-environment package “fscaret”. The input vector was reduced from a total of 135 independent variables to 28. During the modeling stage, techniques like artificial neural networks, genetic programming, rule-based systems, and fuzzy logic systems were used. The 10-fold cross-validation technique was used to assess the generalization ability of the models created. The model obtained had good predictive ability, which was confirmed by a root-mean-square error and normalized root-mean-square error of 4.9 and 11%, respectively. Moreover, validation of the model using external experimental data was performed, and resulted in a root-mean-square error and normalized root-mean-square error of 3.8 and 8.6%, respectively.Published versio