Investigating the Impact of Co-processed Excipients on the Formulation of Bromhexine Hydrochloride Orally Disintegrating Tablets (ODTs).

PURPOSE: Orodispersible tablets (orally disintegrating tablets, ODTs) have been used in pharmacotherapy for over 20 years since they overcome the problems with swallowing solid dosage forms. The successful formula manufactured by direct compression shall ensure acceptable mechanical strength and short disintegration time. Our research aimed to develop ODTs containing bromhexine hydrochloride suitable for registration in accordance with EMA requirements. METHODS: We examined the performance of five multifunctional co-processed excipients, i.e., F-Melt® C, F-Melt® M, Ludiflash®, Pharmaburst® 500 and Prosolv® ODT G2 as well as self-prepared physical blend of directly compressible excipients. We tested powder flow, true density, compaction characteristics and tableting speed sensitivity. RESULTS: The manufacturability studies confirmed that all the co-processed excipients are very effective as the ODT formula constituents. We noticed superior properties of both F-Melt's®, expressed by good mechanical strength of tablets and short disintegration time. Ludiflash® showed excellent performance due to low works of plastic deformation, elastic recovery and ejection. However, the tablets released less than 30% of the drug. Also, the self-prepared blend of excipients was found sufficient for ODT application and successfully transferred to production scale. Outcome of the scale-up trial revealed that the tablets complied with compendial requirements for orodispersible tablets. CONCLUSIONS: We proved that the active ingredient cannot be absorbed in oral cavity and its dissolution profiles in media representing upper part of gastrointestinal tract are similar to marketed immediate release drug product. In our opinion, the developed formula is suitable for registration within the well-established use procedure without necessity of bioequivalence testing.

Nanoemulsion Loaded with Clotrimazole Based on Rapeseed Oil for Potential Vaginal Application-Development, Initial Assessment, and Pilot Release Studies.

Vaginal candidiasis (VC) is an emerging global hardly treated health issue affecting millions of women worldwide. In this study, the nanoemulsion consisting of clotrimazole (CLT), rapeseed oil, Pluronic F-68, Span 80, PEG 200, and lactic acid was prepared using high-speed and high-pressure homogenization. Yielded formulations were characterized by an average droplet size of 52-56 nm, homogenous size distribution by volume, and a polydispersity index (PDI) < 0.2. The osmolality of nanoemulsions (NEs) fulfilled the recommendations of the WHO advisory note. NEs were stable throughout 28 weeks of storage. The stationary and dynamic (USP apparatus IV) pilot study of the changes of free CLT over time for NEs, as well as market cream and CLT suspension as references, were conducted. Test results of the changes in the amount of free CLT released from the encapsulated form were not coherent; in the stationary method, NEs yielded up to 27% of the released CLT dose within 5 h, while in the USP apparatus IV method, NEs released up to 10% of the CLT dose. NEs are promising carriers for vaginal drug delivery in the treatment of VC; however, further development of the final dosage form and harmonized release or dissolution testing protocols are needed.

Dissolution of a Biopharmaceutics Classification System Class II Free Acid from Immediate Release Tablets Containing a Microenvironmental pH Modulator: Comparison of a Biorelevant Bicarbonate Buffering System with Phosphate Buffers.

Poor water dissolution of active pharmaceutical ingredients (API) limits the rate of absorption from the gastrointestinal tract. Increasing the pH of a solid form microenvironment can enhance the dissolution of weakly acidic drugs, but data on this phenomenon in a physiologically relevant bicarbonate media are lacking. In this paper, we examined the effect of a microenvironmental pH modulator (Na2HPO4) on the dissolution of a Biopharmaceutics Classification System (BCS) class II free weak acid (ibuprofen) at biorelevant conditions, including an automatic bicarbonate buffering system, as well as in compendial (50 mM) and low-concentration (10 mM) phosphate buffers with no external pH control. The tablets of 200 mg ibuprofen with either Na2HPO4 (phosphate formulation, PF) or NaCl (reference formulation, RF) were manufactured using a compression method. In a pH 2 simulated gastric fluid, only PF produced a transient supersaturation of ibuprofen, dissolving a fourfold higher drug amount than RF. In a bicarbonate-buffered simulated intestinal fluid with a dynamically controlled pH (5.7, 7.2, and 5.8 to 7.7 gradient), PF dissolved more drug within 30 min than RF (p ≤ 0.019). Of note, the use of a 50 mM phosphate buffer pH 7.2 provided opposite results-RF dissolved the API much faster than PF. Moreover, 10 mM phosphate buffers of pH 5.6 and 7.2 could neither maintain a constant pH nor mimic the bicarbonate buffer performance. In conclusion, the use of a bicarbonate-buffered intestinal fluid, instead of phosphate buffers, may be essential in dissolution tests of BCS class II drugs combined with pH modulators.

Directly compressible formulation of immediate release rosuvastatin calcium tablets stabilized with tribasic calcium phosphate.

Reliable and stable tablet formulations for rosuvastatin calcium (RSC) in four strengths: 5 mg, 10 mg, 20 mg, and 40 mg have been developed. Rosuvastatin is a cholesterol-lowering statin drug and is known to be unstable during storage. The possibility of its stabilization with inorganic salts of multivalent metals has already been reported in the literature. In the present study, a special grade of tribasic calcium phosphate excipient was used to chemically stabilize RSC in a directly compressible immediate release tablet formulation. The developed tablets exhibited good mechanical properties (breaking force ranging from 177 N to 250 N depending on tablet strength), rapid disintegration (less than three minutes) and fast dissolution rate (85% of the drug substance dissolved within 15 minutes) as well as satisfactory chemical stability during storage under stress conditions (50 °C/80% RH), even compared to the reference commercial product.

Foams as unique drug delivery systems.

Foams are multiphase systems found throughout nature. We meet them equally often in our everyday life, starting with the foam in the morning espresso, where the foam should constitute 10% of the drink or in a glass of beer and ending with the evening bath with foam. These multiphase systems consist mainly of gas, which is separated by liquid or solid lamellae. The lamellae have a very large surface area and a small thickness, which results in their low stability. The foams in pharmaceutics are known for a long time as protective or therapeutic preparations for topical use. However, the physicochemical structure of both solid and liquid foams offers multiple fields of application in the modern therapy. For instance, owing to the unique structure, foams can be also used for parenteral use in the form of implants serving as a drug carrier and at the same time, a scaffold for regenerating the tissue. Foams can also be used orally in the form of controlled drug delivery systems that are potentially useful for sustained or targeted drug delivery. The article describes the unique advantages and features of foams that make them useful in modern pharmacotherapy.

Development of a Biphasic-Release Multiple-Unit Pellet System with Diclofenac Sodium Using Novel Calcium Phosphate-Based Starter Pellets.

Novel calcium phosphate-based starter pellets were used to develop a biphasic-release multiple-unit pellet system (MUPS) with diclofenac sodium as a model drug in the form of hard gelatin capsules. For comparative purposes, corresponding formulations based on the inert cores made of microcrystalline cellulose, sucrose and isomalt were prepared. The developed system consisted of two types of drug-layered pellets attaining different release patterns: delayed-release (enteric-coated) and extended-release. Dissolution characteristics were examined using both compendial and biorelevant methods, which reflected fed and fasting conditions. The results were collated with an equivalent commercial product but prepared with the direct pelletization technique.

The influence of physical division of tablets on the variability of release kinetics of gliclazide.

ABSTRACT: Tablets are often used in splitting process when the appropriated, registered dose is not available on the market or patients exhibit swallowing difficulties caused by the size of the tablet. The aim of the work was to assess the impact of physical division of tablets on the kinetics of in vitro gliclazide release from the intact and divided tablets. Gliclazide was released from prolonged release tablets containing 30 or 60 mg of the drug into a phosphate buffer, pH 7.4 and the amount of the drug in acceptor fluid was determined by UV-Vis spectrophotometry. The dissolution profiles were fit to zero- and first-order kinetics as well as to the Korsmeyer-Peppas equation. The largest discrepancy in the values of rate constants was obtained in the case of the release of gliclazide from intact and from splitting tablets using zero- and first-order kinetics. The values of the rate constants k0 obtained from the release of the drug from the intact tablets and from fragments with a dose of the drug of 30 mg were (4.2 ± 0.1) × 10-5 g min-1 and (5.8 ± 0.1) × 10-5 g min-1, respectively, and k1 were (2.3 ± 0.1) × 10-3 min-1 and (4.7 ± 0.6) × 10-3 min-1, respectively. These discrepancies were confirmed by the value of f2 coefficient that was 45.9. The results suggest that physical division of tablets accelerate the release of gliclazide from its prolonged form.

Melts of Octaacetyl Sucrose as Oral-Modified Release Dosage Forms for Delivery of Poorly Soluble Compound in Stable Amorphous Form.

The presented work describes the formulation and characterization of modified release glassy solid dosage forms (GSDFs) containing an amorphous nifedipine, as a model BCS (Biopharmaceutical Classification System) class II drug. The GSDFs were prepared by melting nifedipine together with octaacetyl sucrose. Dissolution profiles, measured under standard and biorelevant conditions, were compared to those obtained from commercially available formulations containing nifedipine such as modified release (MR) tablets and osmotic release oral system (OROS). The results indicate that the dissolution profiles of the GSDFs with nifedipine are neither affected by the pH of the dissolution media, type and concentration of surfactants, nor by simulated mechanical stress of biorelevant intensity. Furthermore, it was found that the dissolution profiles of the novel dosage forms were similar to the profiles obtained from the nifedipine OROS. The formulation of GSDFs is relatively simple, and the dosage forms were found to have favorable dissolution characteristics.

Multimodal approach to characterization of hydrophilic matrices manufactured by wet and dry granulation or direct compression methods.

PURPOSE OF THE RESEARCH: The purpose of the research was to investigate the effect of the manufacturing process of the controlled release hydrophilic matrix tablets on their hydration behavior, internal structure and drug release. Direct compression (DC) quetiapine hemifumarate matrices and matrices made of powders obtained by dry granulation (DG) and high shear wet granulation (HS) were prepared. They had the same quantitative composition and they were evaluated using X-ray microtomography, magnetic resonance imaging and biorelevant stress test dissolution. PRINCIPAL RESULTS: Principal results concerned matrices after 2 h of hydration: (i) layered structure of the DC and DG hydrated tablets with magnetic resonance image intensity decreasing towards the center of the matrix was observed, while in HS matrices layer of lower intensity appeared in the middle of hydrated part; (ii) the DC and DG tablets retained their core and consequently exhibited higher resistance to the physiological stresses during simulation of small intestinal passage than HS formulation. MAJOR CONCLUSIONS: Comparing to DC, HS granulation changed properties of the matrix in terms of hydration pattern and resistance to stress in biorelevant dissolution apparatus. Dry granulation did not change these properties-similar hydration pattern and dissolution in biorelevant conditions were observed for DC and DG matrices.

An understanding of modified release matrix tablets behavior during drug dissolution as the key for prediction of pharmaceutical product performance - case study of multimodal characterization of quetiapine fumarate tablets.

Motivation for the study was the lack of dedicated and effective research and development (R&D) in vitro methods for oral, generic, modified release formulations. The purpose of the research was to assess multimodal in vitro methodology for further bioequivalence study risk minimization. Principal results of the study are as follows: (i) Pharmaceutically equivalent quetiapine fumarate extended release dosage form of Seroquel XR was developed using a quality by design/design of experiment (QbD/DoE) paradigm. (ii) The developed formulation was then compared with originator using X-ray microtomography, magnetic resonance imaging and texture analysis. Despite similarity in terms of compendial dissolution test, developed and original dosage forms differed in micro/meso structure and consequently in mechanical properties. (iii) These differences were found to be the key factors of failure of biorelevant dissolution test using the stress dissolution apparatus. Major conclusions are as follows: (i) Imaging methods allow to assess internal features of the hydrating extended release matrix and together with the stress dissolution test allow to rationalize the design of generic formulations at the in vitro level. (ii) Technological impact on formulation properties e.g., on pore formation in hydrating matrices cannot be overlooked when designing modified release dosage forms.

A novel liquefied gas based oral controlled release drug delivery system for liquid drug formulations.

A novel liquefied gas based drug delivery system for the oral delivery of liquid and semi-solid drug formulations is presented. The capsule-shaped system is equipped with a capillary as an element controlling the release rate. The delivery mechanism is based on a constant vapor pressure produced by isopentane as a low-boiling liquefied gas. The liquid drug valproic acid (VA) was used as a model compound. The viscosity was increased by the addition of povidone (PVP). The VA-PVP gel exhibited pseudoplastic rheological properties, the shear rate was above 0.1s(-1), similar to a Newtonian liquid. The gels tested in the gas based delivery system provided near-zero-order release kinetics. The longest delivery time was up to ca. 8h. The system is characterized by high flexibility of the delivery rate, which can be achieved by adjusting system parameters such as the diameter and length of the capillary, the vapor pressure of the propellant and the viscosity of the drug formulation.

An oral-controlled release drug delivery system for liquid and semisolid drug formulations.

A novel oral drug delivery system for the controlled release of liquid drugs, drug solutions, and semisolid drug preparations is presented that is utilizing the constant vapor pressure of liquefied gas. The system is equipped with a capillary as an element determining the drug delivery rate and contains a liquefied propellant with a suitable boiling point below human body temperature. In the dissolution studies, polyacrylate gels of different viscosities containing paracetamol as model drug were used. Zero-order release kinetics was obtained. The release rates were dependent on the gel viscosity. Besides, by gel viscosity, the drug release rates could also be modified by changing the propellant type and the capillary parameters such as length or diameter. Accordingly, the new system enables a wide range of drug delivery kinetics which can be modified in a case-by-case basis in order to match the desired drug delivery characteristics.