Amal Elkordy

Effects of liquisolid formulations on dissolution of naproxen

The aim of this study was to investigate the use of liquisolid technique in improving the dissolution profiles of naproxen in a solid dosage form. This study was designed to evaluate the effects of different formulation variables, i.e. type of non-volatile liquid vehicles and drug concentrations, on drug dissolution rates. The liquisolid tablets were formulated with three different liquid vehicles, namely Cremophor EL (polyoxyl 35 castor oil), Synperonic PE/L61 (poloxamer 181, polyoxyethylene-polyoxypropylene copolymer) and poly ethylene glycol 400 (PEG400) at two drug concentrations, 20%w/w and 40%w/w. Avicel PH102 was used as a carrier material, Cab-o-sil M-5 as a coating material and maize starch as a disintegrant. The empirical method as introduced by Spireas and Bolton (1999) [1] was applied strictly to calculate the amounts of coating and carrier materials required to prepare naproxen liquisolid tablets. Quality control tests, i.e. uniformity of tablet weight, uniformity of drug content, tablet hardness, friability test, disintegration and dissolution tests were performed to evaluate each batch of prepared tablets. In vitro drug dissolution profiles of the liquisolid formulations were studied and compared with conventional formulation, in simulated gastric fluid (pH 1.2) and simulated intestinal fluid (pH 7.2) without enzyme. Stability studies were carried out to evaluate the stability of the tablets under humid conditions. Differential scanning calorimetry and Fourier transform infrared were used to investigate physicochemical interaction between naproxen and the excipients. It was found that liquisolid tablets formulated with Cremophor EL at drug concentration of 20%w/w produced high dissolution profile with acceptable tablet properties. The stability studies showed that the dissolution profiles of liquisolid tablets prepared with Cremophor EL were not affected by ageing significantly. Furthermore, DSC revealed that drug particles in liquisolid formulations were completely solubilised.

Liquisolid Systems to Improve the Dissolution of Furosemide

A liquisolid system has the ability to improve the dissolution properties of poorly water soluble drugs. Liquisolid compacts are flowing and compactable powdered forms of liquid medications. The aim of this study was to enhance the in vitro dissolution properties of the practically water insoluble loop diuretic furosemide, by utilising liquisolid technique. Several liquisolid tablets were prepared using microcrystalline cellulose (Avicel® pH-101) and fumed silica (Cab-O-Sil® M-5) as the carrier and coating materials, respectively. Polyoxy-ethylene-polyoxypropylene-polyoxyethylene block copolymer (Synperonic® PE/L 81); 1,2,3-propanetriol, homopolymer, (9Z)-9-octadecenoate (Caprol® PGE-860) and polyethylene glycol 400 (PEG 400) were used as non- volatile water-miscible liquid vehicles. The liquid loading factors for such liquid vehicles were calculated to obtain the optimum amounts of carrier and coating materials necessary to produce acceptable flowing and compactible powder admixtures viable to produce compacts. The ratio of carrier to coating material was kept constant in all formulations at 20 to 1. The formulated liquisolid tablets were evaluated for post compaction parameters such as weight variation, hardness, drug content uniformity, percentage friability and disintegration time. The in-vitro release characteristics of the drug from tablets formulated by direct compression (as reference) and liquisolid technique, were studied in two different dissolution media. Differential scanning calorimetry (DSC) and Fourier-Transform infrared spectroscopy (FT-IR) were performed. The results showed that all formulations exhibited higher percentage of drug dissolved in water (pH 6.4–6.6) compared to that at acidic medium (pH 1.2). Liquisolid compacts containing Synperonic® PE/L 81 demonstrated higher release rate at the different pH values. Formulations with PEG 400 displayed lower drug release rate, compared to conventional and liquisolid tablets. DSC and FT-IR indicated a possible interaction between furosemide and tablet excipients that could explain the dissolution results. Caprol® PGE-860, as a liquid vehicle, failed to produce furosemide liquisolid compacts.

Integrity of crystalline lysozyme exceeds that of a spray-dried form

The development of proteins as therapeutic agents is challenging partly due to their inherent instabilities. Consequently, crystallisation and spray drying techniques were assessed to determine their effects on protein integrity using lysozyme as a model protein. Unprocessed, crystallised and spray-dried lysozyme were characterised by: thermal analysis using hot stage microscopy (HSM), differential scanning calorimetry (DSC), high sensitivity differential scanning calorimetry (HSDSC) and thermogravimetry (TGA); and spectroscopic analysis employing Fourier transform Raman (FT-Raman). Moisture contents were determined by TGA and Karl Fisher titration (KFT). Enzymatic assay measured biological activity. HSM showed no changes in crystals until complete melting. TGA and KFT indicated that spray-dried lysozyme contained a lower moisture content than crystals, hence the higher apparent thermal stability was shown by DSC. HSDSC revealed that crystallisation and spray drying did not affect the denaturation temperature of lysozyme in solution when compared with unprocessed material. However, in the solid state, FT-Raman spectra showed perturbation of the conformational structure of spray-dried sample, whereas crystal conformation remained intact. Enzymatic assay revealed increased activity retention of crystals compared with spray-dried powder. Hence, crystals maintained the conformational integrity and activity of lysozyme in solution.

Spironolactone release from liquisolid formulations prepared with Capryol™ 90, Solutol® HS-15 and Kollicoat® SR 30 D as non-volatile liquid vehicles

The purpose of the study is to enhance dissolution of spironolactone as a model hydrophobic drug through application of liquisolid technology. Spironolactone is prepared as liquisolid formulations, and its dissolution property is evaluated and compared to that of conventional spironolactone tablets and pure spironolactone. Three non-volatile liquid vehicles were used in the design of spironolactone liquisolid formulations, Capryol™ 90, Synperonic® PE/L61 in combination with Solutol® HS-15 at a ratio of 1:1, and Kollicoat® SR 30 D. Spironolactone liquisolid formulations were tested according to British Pharmacopoeia (BP) quality control tests. Furthermore, the prepared liquisolid powder formulations were evaluated via differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) and scanning electron microscopy. Also, liquisolid formulations were subjected to testing of storage stability at high relative humidity. The results indicated that most of liquisolid tablets met the BP requirements. Dissolution results indicate that release of spironolactone was significantly increased (P<0.05) through liquisolid formulations, compared to pure drug. Liquisolid powder formulations formulated from a combination of Synperonic® PE/L61-Solutol® HS-15 showed highest dissolution. DSC thermograms from liquisolid formulations revealed that drug endothermic peak was disappeared after processing. Dissolution, DSC and FT-IR data after storage demonstrated that there were no significant changes in the formulations after storage. In conclusion, the liquid vehicles used within spironolactone liquisolid formulations enhanced drug dissolution rate.

Liquisolid technique to enhance and to sustain griseofulvin dissolution: Effect of choice of non-volatile liquid vehicles

Liquisolid systems were originally designed to enhance dissolution of hydrophobic drugs. Recently, the same technique was explored to control drug release via hydrophobic carriers. This work aimed to study the effects of different liquid vehicles on release characteristics of griseofulvin as a model hydrophobic drug. Fast dissolution tablets were prepared using three different non-ionic surfactants namely Cremophor(®)EL, Synperonic(®)PE/L61 and Capryol™ 90, on the contrary Kollicoat(®)SR 30D was used for production of grieseofulvin sustained release formulations. Avicel(®) PH102 and Cab-O-Sil(®) M5 were used as carrier and coat materials, respectively. The effect of formulation parameters, such as drug concentration and carrier to coat ratio, on enhancing drug dissolution was explored. Drug concentrations of 20% and 40% (w/w), and R-values (carrier to coat ratio) of 10 and 20 were used. The mathematical model was utilized to formulate liquisolid powder systems. All fast release liquisolid formulations showed higher percentage drug dissolution efficiency (%DE) than conventional directly compacted tablets. Cremophor(®)EL showed the best dissolution enhancement with %DE of about 90%, compared to only 23% for conventional tablets; DSC data suggested loss of griseofulvin crystallinity and thermal behavior. Kollicoat(®) SR 30D retarded the drug release even in the presence of hydrophilic carrier; DSC data suggested that only small fraction of the drug was present in the molecular state within the system. The used liquisolid vehicles showed promise to enhance and to control (depend on the choice of the liquid vehicle) the release of griseofulvin from liquisolid compacts.

Study of protein conformational stability and integrity using calorimetry and FT-Raman spectroscopy correlated with enzymatic activity

Maintaining protein conformational stability and integrity during formulation is critical for developing protein pharmaceuticals. Accordingly, high sensitivity differential scanning calorimetry (HSDSC) and Fourier transform (FT)-Raman spectroscopy were employed to assess conformational stabilities (thermal stability and folding reversibility) and structural integrities, respectively, for three model proteins: lysozyme, deoxyribonuclease I (DNase I) and lactate dehydrogenase (LDH) in lyophilised (as received) and spray-dried forms. Enzymatic assay after cooling of thermally denatured protein solutions from HSDSC determined if thermal transition reversibility was related to biological activity. HSDSC data showed that molecules from lyophilised lysozyme were able to refold better than the spray-dried form. This was confirmed by enzymatic assay. Moreover, enzymatic assay results revealed that lysozyme folding reversibility was related to the native structure of the protein that is essential for the biological activity. Thermal denaturation of DNase I and LDH samples in HSDSC was not reversible upon cooling of thermally denatured proteins (in contrast to lysozyme). Hence, it was decided to identify the effect of protein initial structures on its propensity to thermal denaturation via FT-Raman spectroscopy. In other words, proteins may denature with structural alterations due to stresses such as heat and the protein loses its enzymatic activity. Consequently, FT-Raman investigated the effects of spray drying and heating of solid DNase I and LDH samples, from differential scanning calorimetry, on protein conformational integrities. Lyophilised and spray-dried DNase I and LDH solid samples were heated to two temperatures, one before the apparent denaturation temperatures (Tm) and the other after the Tm. Samples heated below their Tm showed some alterations of the secondary structure and some enzymatic activity. HSDSC and FT-Raman spectroscopy are useful techniques to study protein conformations and their results correlate with those of enzymatic activity.

Compare and contrast the effects of surfactants (Pluronic®F-127 and Cremophor®EL) and sugars (β-cyclodextrin and inulin) on properties of spray dried and crystallised lysozyme

The stabilisation of proteins using different excipients in dried forms for possible therapeutic use is extensively studied. However, the effects of excipients on proteins in crystallised forms are sparsely documented. Therefore, the influences of PluronicF-127 and CremophorEL (as surfactants) and β-cyclodextrin and inulin (as sugars) on stability and biological activity of lysozyme, a model protein, in spray dried and crystallised forms were investigated. Spray dried and crystallised lysozyme were prepared in absence and presence of the mentioned excipients in a concentration of 0.05% w/v. The protein formulations were characterised in both solution state (using biological assay, particle size analysis and protein concentration determination) and solid state (employing yield determination, scanning electron microscopic (SEM) examination, Fourier transform infrared (FT-IR) spectroscopy for secondary structure analysis and Differential Scanning Calorimetry (DSC) for thermal study). Also, protein samples were assayed for their biological activities after exposing to storage stability study for 20 weeks in solid states at 24 °C/76% relative humidity (RH) and in aqueous states at 24 °C. The results showed that lysozyme crystals with CremophorEL, PluronicF-127, β-cyclodextrin and inulin maintained protein thermal stability (as indicated by DSC) to greater extent compared with spray dried protein formulations. Also, PluronicF-127 was competent to recover 100% lysozyme from crystallisation protein solutions (as confirmed by yield determination); this surfactant was able to prevent aggregate formation within spray dried lysozyme (as demonstrated by particle size analysis). The presence of PluronicF-127, β-cyclodextrin and inulin preserved the protein biological activity in freshly prepared spray dried and crystallised samples. PluronicF-127 was competent to protect lysozyme in both spray dried and crystallised forms after storage. PluronicF-127 has proved to be a promising protectant of proteins. The improved stability of the spray dried and crystallised protein containing PluronicF-127 shows promise for delivery of proteins via inhalation (in a spray dried form which has particle size range suitable for inhalation as revealed by particle size analysis and SEM) and injectable routes (in spray dried and crystallised forms). The way excipients react with proteins is different in the case of spray drying and crystallisation techniques, hence the choice of the additives and the processing techniques play a great role in controlling protein properties, activity and stability as shown in this study.

In situ controlled crystallization as a tool to improve the dissolution of Glibenclamide

For pharmaceutical purpose, micro-sized drugs are needed for many delivery systems, such as pulmonary and oral drug delivery systems. Many strategies have been employed to reduce the particle size of poorly water soluble drugs. Microcrystals could be produced by controlled association of drug in order to obtain naturally grown particles. The aim of this work was to increase the aqueous solubility and dissolution of Glibenclamide. The in situ controlled crystallization process was conducted in the presence of the non-ionic surfactants, Cremophor RH40 and Solutol HS-15 (0.75 and 1.5%, w/v), as protective stabilizing agents against agglomeration. In addition, these surfactants inhibit P-glycoprotein that reduces intestinal absorption of Glibenclamide by efflux transportation. Crystal shape was changed and particle size was reduced by about 15-folds, compared to control untreated drug. Differential Scanning Calorimetry (DSC) results indicated no interaction between the drug and the stabilizer. Microcrystals showed marked increase in the drug dissolution, Solutol HS-15 at 1.5% (w/v) concentration showing the highest dissolution efficiency. It could be concluded that in situ controlled crystallization using surfactants are promising method to improve dissolution of Glibeclamide as a model poorly water soluble drug.

Design and evaluation of effervescent floating tablets based on hydroxyethyl cellulose and sodium alginate using pentoxifylline as a model drug

The aim of this work was to design and evaluate effervescent floating gastro-retentive drug delivery matrix tablets with sustained-release behavior using a binary mixture of hydroxyethyl cellulose and sodium alginate. Pentoxifylline was used as a highly water-soluble, short half-life model drug with a high density. The floating capacity, swelling, and drug release behaviors of drug-loaded matrix tablets were evaluated in 0.1 N HCl (pH 1.2) at 37°C±0.5°C. Release data were analyzed by fitting the power law model of Korsmeyer–Peppas. The effect of different formulation variables was investigated, such as wet granulation, sodium bicarbonate gas-forming agent level, and tablet hardness properties. Statistical analysis was applied by paired sample t-test and one-way analysis of variance depending on the type of data to determine significant effect of different parameters. All prepared tablets through wet granulation showed acceptable physicochemical properties and their drug release profiles followed non-Fickian diffusion. They could float on the surface of dissolution medium and sustain drug release over 24 hours. Tablets prepared with 20% w/w sodium bicarbonate at 50–54 N hardness were promising with respect to their floating lag time, floating duration, swelling ability, and sustained drug release profile.

Formulation and advantages of furazolidone in liposomal drug delivery systems

Furazolidone has proven to have antiprotozoal and antibacterial activity. A number of literature supported its use against Helicobacter pylori. This potential application opens new prospects of its use in clinical settings in triple therapy. In order to avoid side effects associated with this drug, liposomal mucoadhesive drug delivery that can work locally in stomach is considered as an appropriate approach. This study is a focus on formulations and in vitro characterization of liposomes containing furazolidone. Therefore, the effects of variable amounts of drug and cholesterol on encapsulation efficacy and in vitro drug release were evaluated for different liposomal formulations. Mucoadhesive behavior of chitosan coated liposomal at two different pHs was also evaluated and increase in pH from 1.3 to 4.5 increased mucoadhesion from 42% to 60% respectively. Increasing the amount of drug from 4mg to 5mg increased encapsulation activity however, increasing the drug any further decreased encapsulation activity. In contrast, by increasing the amount of cholesterol decrease in encapsulation activity was observed. The optimized formulation with 5mg of drug and 53mg of cholesterol in formulation gave 57% drug release at pH 1.3 but release was increased up to 71% by increasing pH to 4.5 for same amount of drug. However, by using 10.6mg of cholesterol and 5mg of drug the overall release was increased at both pH conditions, at pH 1.3 release was 69% as compared to 77% at pH 4.5. This trend of drug release profile and mucoadhesion that favors pH 4.5 is documented as useful in targeting H. pylori as normal pH of stomach is expected to be higher by the influence of this microbe. Hence, the results of this research can be taken further into a future in vivo study.