Introduction: As dissolution plays an important and vital role in the drug-delivery process of or... more Introduction: As dissolution plays an important and vital role in the drug-delivery process of oral solid dosage forms, it is, therefore, essential to critically evaluate the parameters that can affect this process. Areas covered: The consumption of food as well as the physiological environment and properties of the gastrointestinal tract, such as its volume and composition of fluid, the fluid hydrodynamics, properties of the intestinal membrane, drug dose and solubility, pK a , diffusion coefficient, permeability and particle size, all affect drug dissolution and absorption rate. There are several dissolution approaches that have been developed to address the conditions as experienced in the in vivo environment, as the traditional dissolution being a quality control method is not biorelevant and as such do not always produce meaningful data. This review also describes the development of a systematic way that differentiates between robust and non-robust formulations by varying the effects of agitation and ionic strength through the use of the automated United States Pharmacopeia type III Bio-Dis apparatus. Expert opinion: With the improved understanding of the physiological parameters that can affect the oral bioperformance of dosage forms, strides have, therefore, been made in making dissolution testing methods more biologically based with the view of obtaining more in vitro-in vivo correlations.
The buccal mucosa has been investigated for local and systemic delivery of therapeutic peptides a... more The buccal mucosa has been investigated for local and systemic delivery of therapeutic peptides and other drugs that are subjected to first-pass metabolism or are unstable within the rest of the gastrointestinal tract. Propranolol hydrochloride (propranolol HCl) is subjected to first-pass effect, therefore formulation of buccal-adhesive dosage form can circumvent this effect. The effect of lactose (a soluble excipient) and dicalcium phosphate (DCP) (an insoluble excipient) on dissolution rate, kinetic of release and adhesion force of buccal-adhesive tablets of propranolol HCl were evaluated. Each tablet composed of 80 mg propranolol HCl, 80 mg hydroxypropylmethylcellulose (HPMC) K4M, polycarbophil AA1 and lactose or DCP with different ratios. The results showed that the presence of the fillers increased dissolution rate of the drug. The release data also showed that the effect of lactose on the dissolution rate was greater than the DCP. Kinetic release of propranolol HCl from buccal-adhesive matrices was affected by the different ratios of polymers and fillers. The fillers reduced the bioadhesion force and this effect was more considerable in formulation containing DCP. In order to determine the mode of release, the data were analyzed based on the equation Q =kt n . The results showed that an increase in the concentration of HPMC K4M resulted in a reduction in the value of n. The value of n was not significantly affected by an increase in the concentration of lactose or DCP. The values of n in this study were calculated to be between 0.461 and 0.619, indicating both diffusional release and erosional mechanism.
International Journal of Pharmaceutics, Jan 27, 2014
Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor ... more Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C±1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
The aim of this work was to investigate the mechanistic evaluation of physicochemical properties ... more The aim of this work was to investigate the mechanistic evaluation of physicochemical properties of new engineered lactose on aerosolisation performance of salbutamol sulphate (SS) delivered from dry powder inhaler (DPI). Different crystallised lactose particles were obtained from binary mixtures of butanol:acetone. The sieved fractions (63-90 m) of crystallised lactose were characterised in terms of size, shape, flowability, true density and aerosolisation performance (using multiple twin stage impinger (MSLI), Aerolizer ® inhaler device, and salbutamol sulphate as a model drug). Compared to commercial lactose, crystallised lactose particles were less elongated, covered with fine lactose particles, and had a rougher surface morphology. The crystallised lactose powders had a considerably lower bulk and tap density and poorer flow when compared to commercial lactose. Engineered carrier with better flow showed improved drug content homogeneity, reduced amounts of drug "deposited" on the inhaler device and throat, and a smaller drug aerodynamic diameter upon inhalation. Aerodynamic diameter of salbutamol sulphate increased as lactose aerodynamic diameter decreased (linear, R 2 = 0.9191) and/or as fine particle lactose content increased (linear, R 2 = 0.8653). Improved drug aerosolisation performance in the case of crystallised lactose particles was attributed to lower drug-carrier adhesion forces due to a rougher surface and higher fine particle content. In conclusion, this work proved that using binary combinations of solvents in crystallisation medium is vital in modification of the physicochemical and micromeritic properties of carriers to achieve a desirable aerosolisation performance from DPI formulations. Among all lactose samples, lactose particles crystallised from pure butanol generated the highest overall DPI formulations desirability.
Crystallised mannitol carriers from different binary mixtures of acetone/water were prepared and ... more Crystallised mannitol carriers from different binary mixtures of acetone/water were prepared and investigated. Crystallised mannitol particles were more elongated, with different polymorphic form, poorer flowability, and considerably better aerosolisation performance than that of the commercial mannitol formulation blends. It was shown that, generally, carriers having a high tapped density and high fraction of fine mannitol particles produced a high FPF. Abbreviations-API: Active pharmaceutical ingredient, CI: Carr's Index, CV: Coefficient of variation, DPI: Dry powder inhaler, DSC: Different scanning calorimetry, FPF: Fine particle fraction, FT-IR: Fourier Transform infra red, SEM: Scanning electron microscope. S v : volume specific surface area, ρ true : true density, ρ bulk : bulk density, ρ tap : tap density.
Dry powder inhaler formulations comprising commercial lactose-drug blends can show restricted det... more Dry powder inhaler formulations comprising commercial lactose-drug blends can show restricted detachment of drug from lactose during aerosolisation, which can lead to poor fine particle fractions (FPFs) which are suboptimal. The aim of the present study was to investigate whether the crystallisation of lactose from different ethanol/butanol co-solvent mixtures could be employed as a method of altering the FPF of salbutamol sulphate from powder blends. Lactose particles were prepared by an anti-solvent recrystallisation process using various ratios of the two solvents. Crystallised lactose or commercial lactose was mixed with salbutamol sulphate and in vitro deposition studies were performed using a multistage liquid impinger. Solid-state characterisation results showed that commercial lactose was primarily composed of the α-anomer whilst the crystallised lactose samples comprised a α/β mixture containing a lower number of moles of water per mole of lactose compared to the commercial lactose. The crystallised lactose particles were also less elongated and more irregular in shape with rougher surfaces. Formulation blends containing crystallised lactose showed better aerosolisation performance and dose uniformity when compared to commercial lactose. The highest FPF of salbutamol sulphate (38.0±2.5%) was obtained for the lactose samples that were crystallised from a mixture of ethanol/butanol (20:60) compared to a FPF of 19.7±1.9% obtained for commercial lactose. Engineered lactose carriers with modified anomer content and physicochemical properties, when compared to the commercial grade, produced formulations which generated a high FPF.
This investigation is aimed at characterization of the mode of release from two different substit... more This investigation is aimed at characterization of the mode of release from two different substitution types of HPMC and the effect of chemical structure of drugs using the QSPR (Quantitative -Structure-Property Relationship) technique. To this end, release profiles of HPMC matrices of several drugs containing the same formulation and compressed at a constant pressure were studied. QSPR method was used to establish statistically significant relationships between release parameters and the structural descriptors. Structural descriptors consisted of molecular mechanical, quantum mechanical and graph-theoretical parameters, as well as the partition coefficient and the aqueous solubility of the drugs. The results showed that the most important factors determining the release profile from both HPMC K4M and HPMC E4M matrices were the aqueous solubility of drugs (which could be substituted efficiently by dipole moment) and the size of the drug molecules. Comparison of drug release from matrices prepared using the two grades of HPMC showed very distinct differences for some drugs, as evaluated by the similarity factor. The results indicated that the source of the difference could be sought in the drug properties (as exemplified by the aqueous solubility and surface area) as well as the rate of erosion (that depends mainly on the polymer type). ß
International Journal of Pharmaceutics, Jan 30, 2013
Electrostatic charge is generated during powder handling due to particle-particle and particle-wa... more Electrostatic charge is generated during powder handling due to particle-particle and particle-wall collisions, rubbing, sliding, and rolling. In case of bipolar charge generation, the electrostatic forces may significantly change the inner forces and increase powder adhesion and cause a serious problem in material handling process. Therefore, the knowledge of distribution of charge across the individual particles is helpful to identify the role of triboelectrification and the effects of various relevant variables especially change in the contact materials, environmental conditions during processing, etc. A novel approach based on inductive sensor has been developed to detect the either polarity of charged particle and to characterise the bipolar charge distribution in the population of particulate material. To achieve this, an amplification unit configured as a pure integrator and signal processing techniques has been used to de-noise and correct the baseline of signal and MATLAB algorithm developed for peak detection. The polarity of charged particles obtained by this method is calibrated with Faraday pail method and the results are promising. Experimental study has been carried out by using two distinct populations of oppositely charged particles (glass beads-PVC, olivine sand, and silica sand). The obtained results indicate that the method is able to detect the distribution of polarities of charged particles.
International Journal of Pharmaceutics, Apr 1, 2010
The aim of the present study was to investigate the effect of crystallising mannitol from differe... more The aim of the present study was to investigate the effect of crystallising mannitol from different binary mixtures of acetone/water on the resultant physical properties and to determine the effects of any changes on in vitro aerosolisation performance, when the different mannitol crystals were used as a carrier in dry powder inhaler formulations containing salbutamol sulphate. Mannitol particles were crystallised under controlled conditions by dissolving the sugar in water and precipitating the sugar using binary mixtures of acetone/water in different percentages as anti-solvent media. For comparison purposes the physical properties and deposition behaviour of commercially available mannitol were also studied. SEM showed that all crystallised mannitol particles were more elongated than the commercial mannitol. Solid state studies revealed that commercial mannitol and mannitol crystallised using acetone in the presence of 10-25% v/v water as anti-solvent was -polymorphic form whereas mannitol crystallised in the presence of a small amount of water (0-7.5%) was the ␣-form. All the crystallised mannitol samples showed poor flowability. Nevertheless, the powdered crystallised mannitol and commercial samples were blended with salbutamol in the ratio 67.5:1. The aerosolisation performance of the formulations containing the engineered mannitol (evaluated using Multi Stage Liquid Impinger) was considerably better than that of the commercial mannitol formulation (the fine particle fraction was increased from 15.42% to 33.07-43.99%, for the formulations containing crystallised mannitol). Generally, carriers having a high tapped density and high fraction of fine carrier particles produced a high FPF. The improvement in the DPI performance could be attributed to the presence of elongated carrier particles with smooth surfaces since these are believed to have less adhesive forces between carrier and the drug resulting in easier detachment of the drug during the inhalation.
Journal of Aerosol Medicine and Pulmonary Drug Delivery, May 20, 2013
ABSTRACT Higher fine particle fractions of the drug were obtained for lactose powders with higher... more ABSTRACT Higher fine particle fractions of the drug were obtained for lactose powders with higher porosity, and lactose particles with higher specific surface area and higher fine particle content (<5 µm). With increasing the saturation degree of lactose solution used during crystallization, the specific surface area of lactose particles was reduced, whereas the amorphous lactose and β-lactose contents were increased. Thus, this study demonstrated that it is possible to prepare engineered lacrosse particles with favourable properties for DPI formulations using lactose solutions with a low degree of saturation during crystallization.
Delivery of two drugs in one dry powder inhaler (DPI) is expected to play an increasing and more ... more Delivery of two drugs in one dry powder inhaler (DPI) is expected to play an increasing and more effective role in the management of asthma and chronic obstructive pulmonary disease. In this study we investigated five sugars as possible carriers of both budesonide, an anti-inflammatory glucocorticoid, and formoterol, a long-acting β agonist, in one DPI formulation. Most DPI formulations utilise lactose as a carrier in the drug-carrier blends; however, it cannot be used for compounds that react with its reducing group, such as budesonide, formoterol, or peptide/proteinbased drugs. Therefore, alternative carriers such as sorbitol, mannitol, dextrose and xylitol were selected for this study in addition to lactose, which was used as a reference. A formulation comprising 5% w/w budesonide and 0.3% w/w formoterol was prepared with each sugar. The carriers were sieved to obtain 63-90 µm fractions and physicochemically characterised via true density, powder flow, particle size and surface morphology analyses. The dispersion and deaggregation of the two drugs from the five formulations were assessed after aerosolisation at 58-68 L min-1 via a device-metered Airmax inhaler into a Multi-Stage Liquid Impinger. The findings show that the deposition efficiencies of the five formulations were influenced by the particle size distribution, surface morphology and flowability of the respective carriers, and that mannitol showed the greatest potential as an alternative carrier to lactose. Mannitol produced the highest fine particle fraction values of 72.4% and 27.5% for budesonide and formoterol, respectively, and this performance was largely attributable to the relatively high percentage of fine particles (< 10.50 µm) compared to the other carriers.
Http Dx Doi Org 10 3109 10837450903002173, Jan 21, 2010
Ethylcellulose microparticles containing tolmetin sodium, an anti-inflammatory drug, were prepare... more Ethylcellulose microparticles containing tolmetin sodium, an anti-inflammatory drug, were prepared by a solvent diffusion method based on the formation of multiple W/O(1)/O(2)-emulsion. The drug used was TOL, which is water-soluble and n-hexane was used as the non-solvent. Important parameters in the evaluation of a microencapsulation technique are actual drug loading, the encapsulation efficiency, the yield, solvent systems, dispersed phase to continuous phase ratio (DP/CP ratio), composition of continuous phase, drug distribution in microparticles and stability of primary emulsion. A small volume of internal aqueous phase and volume of organic solvent were favorable to achieve high drug encapsulation efficiencies. Since drug release during the initial stages depends mostly on the diffusion escape of the drug, major approaches to prevent the initial burst have focused on efficient encapsulation of the drug within the microparticles. For this reason, control of efficiency and the extent of initial burst are based on common formulation parameters. Most parameters affect encapsulation efficiency and initial burst by modifying solidification rate of dispersed phase. In order to prevent many unfavorable events such as pore formation, drug loss, and drug migration that occur while the dispersed phase is in the semi-solid state, it is important to understand and optimize these variables.
The aim of this study was to evaluate microencapsulated controlled release preparations of tolmet... more The aim of this study was to evaluate microencapsulated controlled release preparations of tolmetin sodium using ethylcellulose as a retardant material. Microspheres were prepared by using water-in-oil-in-oil (W/O(1)/O(2)) double-emulsion solvent diffusion method, using different ratios of ethylcellulose to tolmetin sodium. Span 80 was used as the droplet stabilizer and n-hexane was added to harden the microspheres. The prepared microspheres were characterized for their micromeritic properties, drug content, loading efficiency, production yield, and particle size. Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy were used to characterize microparticles. The in vitro release studies were performed in pH 1.2 and 7.4. The prepared microspheres were spherical in shape. The drug-loaded microspheres showed near to the theoretical of entrapment and release was extended up to 24. The X-ray diffractogram and differential scanning thermographs showed amorphous state of the drug in the microspheres. It was shown that the drug: polymer ratio, stirring rate, volume of dispersing medium and surfactant influenced the drug loading, particle size and drug release behavior of the formed microparticles. The results showed that, generally, an increase in the ratio of drug: polymer (0.5:1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The in vitro release profile could be modified by changing various processing and formulation parameters to give a controlled release of drug from the microparticules. The release of tolmetin was influenced by the drug to polymer ratio and particle size and was found to be diffusion and erosion controlled. The best-fit release kinetic was achieved with Peppas model.
The purpose of this investigation was to evaluate microencapsulated controlled release preparatio... more The purpose of this investigation was to evaluate microencapsulated controlled release preparation of theophylline using Eudragit RS 100 as the retardant material with high entrapment efficiency. Microspheres were prepared by the emulsion-solvent evaporation method. A mixed solvent system consisting of methanol and acetone and light liquid paraffin as oily phase were chosen. Sucrose stearate was used as the surfactant to stabilize the emulsification process. The prepared microspheres were characterized by drug loading, Fourier-transform infrared spectroscopy (FTIR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release studies were performed at pH 1.2 and 7.4 aqueous medium. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release rate. The drug loading microparticle Eudragit RS100(1:6) showed 60-75% of entrapment and mean particle size 205.93-352.76 μm.The results showed that, an increase in the ratio of polymer: drug (F5, 6: 1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The release of theophylline is influenced by the drug to polymer ratio and particle size. Drug release is controlled by diffusion and the best-fit release kinetic is Higuchi model.
Hard gelatin capsule was coated by a cellulose acetate as a semipermeable membrane with or withou... more Hard gelatin capsule was coated by a cellulose acetate as a semipermeable membrane with or without castor oil and filled with propranolol hydrochloride and sorbitol as an osmotic agent. After sealing the capsule with white bees wax plug, the onset of release and dissolution rate of the drug were studied. Water penetration into the capsule from the dissolution medium increases simultaneously the osmotic and hydrostatic pressures of its content. When the hydrostatic pressure is high enough to overweigh the gravity and frictional forces of the plug, the expulsion of the plug occurs and drug release starts. The effects of thicknesses of the membrane and plug as well as the concentrations of cellulose acetate and castor oil on the onset of drug release were presented by a polynomial model. We found that the effect of plug thickness on the onset of release is more important when the membrane is thicker. The results showed that the presence of caster oil in coating formulation (cellulose acetate 10% or 15%) increased the onset of release (t(o) values). The onset of release varied from 0.6 to 10.5 hr among which the onset times of 4.2, 4.8, 5.9, 5.5, 7.5, 5.0, 7.8 and 10.5 hr could be of use for either chronotherapeutic purposes in protection of patients against heart attacks and strokes during early morning hours or reducing daily frequency of dosage.
International Journal of Pharmaceutics, Feb 3, 2006
Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and ath... more Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and athletes foot. Skin irritation is a common side effect, and it has been shown that controlled release of BPO from a delivery system to the skin could reduce the side effect while reducing percutaneous absorption. Therefore, the aim of the present study was to produce ethylcellulose microparticles containing BPO which were able to control the release of BPO to the skin. In order to optimize the microparticle formulation, factors affecting the physical properties of microparticles were also investigated. Benzoyl peroxide microparticles were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol. Drug content, particle size analysis and loading yield were determined in the prepared microparticles. BPO microparticles were then incorporated into standard vehicles for release studies. Scanning electron microscopy was used to study the shape and morphology of the microsponges. The micrograph of microsponges showed that they were spherical in shape and contained pores. These pores resulted from the diffusion of solvent from the surface of the microparticles and thus the particles were designated as microsponges. It was shown that the drug:polymer ratio, stirring rate, volume of dispersed phase influenced the particle size and drug release behavior of the formed microsponges and that the presence of emulsifier was essential for microsponge formation. The results showed that, generally, an increase in the ratio of drug:polymer resulted in a reduction in the release rate of BPO from microsponges which was attributed to a decreased internal porosity of the microsponges.
Http Dx Doi Org 10 3109 03639045 2014 991401, Dec 11, 2014
The cogrinding technique is one of most effective methods for improving the dissolution of poorly... more The cogrinding technique is one of most effective methods for improving the dissolution of poorly water soluble drugs and it is superior to other approaches from an economical as well as an environmental stand point, as the technique does not require any toxic organic solvents.
Introduction: As dissolution plays an important and vital role in the drug-delivery process of or... more Introduction: As dissolution plays an important and vital role in the drug-delivery process of oral solid dosage forms, it is, therefore, essential to critically evaluate the parameters that can affect this process. Areas covered: The consumption of food as well as the physiological environment and properties of the gastrointestinal tract, such as its volume and composition of fluid, the fluid hydrodynamics, properties of the intestinal membrane, drug dose and solubility, pK a , diffusion coefficient, permeability and particle size, all affect drug dissolution and absorption rate. There are several dissolution approaches that have been developed to address the conditions as experienced in the in vivo environment, as the traditional dissolution being a quality control method is not biorelevant and as such do not always produce meaningful data. This review also describes the development of a systematic way that differentiates between robust and non-robust formulations by varying the effects of agitation and ionic strength through the use of the automated United States Pharmacopeia type III Bio-Dis apparatus. Expert opinion: With the improved understanding of the physiological parameters that can affect the oral bioperformance of dosage forms, strides have, therefore, been made in making dissolution testing methods more biologically based with the view of obtaining more in vitro-in vivo correlations.
The buccal mucosa has been investigated for local and systemic delivery of therapeutic peptides a... more The buccal mucosa has been investigated for local and systemic delivery of therapeutic peptides and other drugs that are subjected to first-pass metabolism or are unstable within the rest of the gastrointestinal tract. Propranolol hydrochloride (propranolol HCl) is subjected to first-pass effect, therefore formulation of buccal-adhesive dosage form can circumvent this effect. The effect of lactose (a soluble excipient) and dicalcium phosphate (DCP) (an insoluble excipient) on dissolution rate, kinetic of release and adhesion force of buccal-adhesive tablets of propranolol HCl were evaluated. Each tablet composed of 80 mg propranolol HCl, 80 mg hydroxypropylmethylcellulose (HPMC) K4M, polycarbophil AA1 and lactose or DCP with different ratios. The results showed that the presence of the fillers increased dissolution rate of the drug. The release data also showed that the effect of lactose on the dissolution rate was greater than the DCP. Kinetic release of propranolol HCl from buccal-adhesive matrices was affected by the different ratios of polymers and fillers. The fillers reduced the bioadhesion force and this effect was more considerable in formulation containing DCP. In order to determine the mode of release, the data were analyzed based on the equation Q =kt n . The results showed that an increase in the concentration of HPMC K4M resulted in a reduction in the value of n. The value of n was not significantly affected by an increase in the concentration of lactose or DCP. The values of n in this study were calculated to be between 0.461 and 0.619, indicating both diffusional release and erosional mechanism.
International Journal of Pharmaceutics, Jan 27, 2014
Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor ... more Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.
Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temp... more Matrices containing PEO fail to provide stable drug release profiles when stored at elevated temperatures for a period of time. The present study aims to stabilize diltiazem HCl release from matrices made from various molecular weights of polyox powders. To this end, various molecular weights of polyox with and without vitamin E (0.25, 0.5 and 1% w/w) were stored at 40°C for 0, 2, 4 and 8 weeks. The aged polyox powders were then mixed with the model drug at a ratio of 1:1 and compressed into tablets. At different time intervals, the aged polyox with vitamin E were taken out of oven and mixed with the drug (1:1 ratio) and compressed into tablets. Dissolution studies showed a significant increase in diltiazem HCl release rate to occur with increased storage time at 40°C±1 from tablets made from the aged polyox (no vitamin E). This was as a result of depolymerization of the aged polyox powders as compared to the fresh polyox samples. This was confirmed by differential scanning calorimetry (DSC) which showed a reduction in the melting point of the aged samples. Concentrations of vitamin E as low as 0.25% w/w was able to overcome the quick release of drug from the matrices made from aged polyox powders. DSC traces showed that the melting point of aged polyox samples containing vitamin E remained the same as that of the fresh samples. The presence of vitamin E is essential to stabilize the drug release from polyox matrices containing diltiazem HCl.
The aim of this work was to investigate the mechanistic evaluation of physicochemical properties ... more The aim of this work was to investigate the mechanistic evaluation of physicochemical properties of new engineered lactose on aerosolisation performance of salbutamol sulphate (SS) delivered from dry powder inhaler (DPI). Different crystallised lactose particles were obtained from binary mixtures of butanol:acetone. The sieved fractions (63-90 m) of crystallised lactose were characterised in terms of size, shape, flowability, true density and aerosolisation performance (using multiple twin stage impinger (MSLI), Aerolizer ® inhaler device, and salbutamol sulphate as a model drug). Compared to commercial lactose, crystallised lactose particles were less elongated, covered with fine lactose particles, and had a rougher surface morphology. The crystallised lactose powders had a considerably lower bulk and tap density and poorer flow when compared to commercial lactose. Engineered carrier with better flow showed improved drug content homogeneity, reduced amounts of drug "deposited" on the inhaler device and throat, and a smaller drug aerodynamic diameter upon inhalation. Aerodynamic diameter of salbutamol sulphate increased as lactose aerodynamic diameter decreased (linear, R 2 = 0.9191) and/or as fine particle lactose content increased (linear, R 2 = 0.8653). Improved drug aerosolisation performance in the case of crystallised lactose particles was attributed to lower drug-carrier adhesion forces due to a rougher surface and higher fine particle content. In conclusion, this work proved that using binary combinations of solvents in crystallisation medium is vital in modification of the physicochemical and micromeritic properties of carriers to achieve a desirable aerosolisation performance from DPI formulations. Among all lactose samples, lactose particles crystallised from pure butanol generated the highest overall DPI formulations desirability.
Crystallised mannitol carriers from different binary mixtures of acetone/water were prepared and ... more Crystallised mannitol carriers from different binary mixtures of acetone/water were prepared and investigated. Crystallised mannitol particles were more elongated, with different polymorphic form, poorer flowability, and considerably better aerosolisation performance than that of the commercial mannitol formulation blends. It was shown that, generally, carriers having a high tapped density and high fraction of fine mannitol particles produced a high FPF. Abbreviations-API: Active pharmaceutical ingredient, CI: Carr's Index, CV: Coefficient of variation, DPI: Dry powder inhaler, DSC: Different scanning calorimetry, FPF: Fine particle fraction, FT-IR: Fourier Transform infra red, SEM: Scanning electron microscope. S v : volume specific surface area, ρ true : true density, ρ bulk : bulk density, ρ tap : tap density.
Dry powder inhaler formulations comprising commercial lactose-drug blends can show restricted det... more Dry powder inhaler formulations comprising commercial lactose-drug blends can show restricted detachment of drug from lactose during aerosolisation, which can lead to poor fine particle fractions (FPFs) which are suboptimal. The aim of the present study was to investigate whether the crystallisation of lactose from different ethanol/butanol co-solvent mixtures could be employed as a method of altering the FPF of salbutamol sulphate from powder blends. Lactose particles were prepared by an anti-solvent recrystallisation process using various ratios of the two solvents. Crystallised lactose or commercial lactose was mixed with salbutamol sulphate and in vitro deposition studies were performed using a multistage liquid impinger. Solid-state characterisation results showed that commercial lactose was primarily composed of the α-anomer whilst the crystallised lactose samples comprised a α/β mixture containing a lower number of moles of water per mole of lactose compared to the commercial lactose. The crystallised lactose particles were also less elongated and more irregular in shape with rougher surfaces. Formulation blends containing crystallised lactose showed better aerosolisation performance and dose uniformity when compared to commercial lactose. The highest FPF of salbutamol sulphate (38.0±2.5%) was obtained for the lactose samples that were crystallised from a mixture of ethanol/butanol (20:60) compared to a FPF of 19.7±1.9% obtained for commercial lactose. Engineered lactose carriers with modified anomer content and physicochemical properties, when compared to the commercial grade, produced formulations which generated a high FPF.
This investigation is aimed at characterization of the mode of release from two different substit... more This investigation is aimed at characterization of the mode of release from two different substitution types of HPMC and the effect of chemical structure of drugs using the QSPR (Quantitative -Structure-Property Relationship) technique. To this end, release profiles of HPMC matrices of several drugs containing the same formulation and compressed at a constant pressure were studied. QSPR method was used to establish statistically significant relationships between release parameters and the structural descriptors. Structural descriptors consisted of molecular mechanical, quantum mechanical and graph-theoretical parameters, as well as the partition coefficient and the aqueous solubility of the drugs. The results showed that the most important factors determining the release profile from both HPMC K4M and HPMC E4M matrices were the aqueous solubility of drugs (which could be substituted efficiently by dipole moment) and the size of the drug molecules. Comparison of drug release from matrices prepared using the two grades of HPMC showed very distinct differences for some drugs, as evaluated by the similarity factor. The results indicated that the source of the difference could be sought in the drug properties (as exemplified by the aqueous solubility and surface area) as well as the rate of erosion (that depends mainly on the polymer type). ß
International Journal of Pharmaceutics, Jan 30, 2013
Electrostatic charge is generated during powder handling due to particle-particle and particle-wa... more Electrostatic charge is generated during powder handling due to particle-particle and particle-wall collisions, rubbing, sliding, and rolling. In case of bipolar charge generation, the electrostatic forces may significantly change the inner forces and increase powder adhesion and cause a serious problem in material handling process. Therefore, the knowledge of distribution of charge across the individual particles is helpful to identify the role of triboelectrification and the effects of various relevant variables especially change in the contact materials, environmental conditions during processing, etc. A novel approach based on inductive sensor has been developed to detect the either polarity of charged particle and to characterise the bipolar charge distribution in the population of particulate material. To achieve this, an amplification unit configured as a pure integrator and signal processing techniques has been used to de-noise and correct the baseline of signal and MATLAB algorithm developed for peak detection. The polarity of charged particles obtained by this method is calibrated with Faraday pail method and the results are promising. Experimental study has been carried out by using two distinct populations of oppositely charged particles (glass beads-PVC, olivine sand, and silica sand). The obtained results indicate that the method is able to detect the distribution of polarities of charged particles.
International Journal of Pharmaceutics, Apr 1, 2010
The aim of the present study was to investigate the effect of crystallising mannitol from differe... more The aim of the present study was to investigate the effect of crystallising mannitol from different binary mixtures of acetone/water on the resultant physical properties and to determine the effects of any changes on in vitro aerosolisation performance, when the different mannitol crystals were used as a carrier in dry powder inhaler formulations containing salbutamol sulphate. Mannitol particles were crystallised under controlled conditions by dissolving the sugar in water and precipitating the sugar using binary mixtures of acetone/water in different percentages as anti-solvent media. For comparison purposes the physical properties and deposition behaviour of commercially available mannitol were also studied. SEM showed that all crystallised mannitol particles were more elongated than the commercial mannitol. Solid state studies revealed that commercial mannitol and mannitol crystallised using acetone in the presence of 10-25% v/v water as anti-solvent was -polymorphic form whereas mannitol crystallised in the presence of a small amount of water (0-7.5%) was the ␣-form. All the crystallised mannitol samples showed poor flowability. Nevertheless, the powdered crystallised mannitol and commercial samples were blended with salbutamol in the ratio 67.5:1. The aerosolisation performance of the formulations containing the engineered mannitol (evaluated using Multi Stage Liquid Impinger) was considerably better than that of the commercial mannitol formulation (the fine particle fraction was increased from 15.42% to 33.07-43.99%, for the formulations containing crystallised mannitol). Generally, carriers having a high tapped density and high fraction of fine carrier particles produced a high FPF. The improvement in the DPI performance could be attributed to the presence of elongated carrier particles with smooth surfaces since these are believed to have less adhesive forces between carrier and the drug resulting in easier detachment of the drug during the inhalation.
Journal of Aerosol Medicine and Pulmonary Drug Delivery, May 20, 2013
ABSTRACT Higher fine particle fractions of the drug were obtained for lactose powders with higher... more ABSTRACT Higher fine particle fractions of the drug were obtained for lactose powders with higher porosity, and lactose particles with higher specific surface area and higher fine particle content (&lt;5 µm). With increasing the saturation degree of lactose solution used during crystallization, the specific surface area of lactose particles was reduced, whereas the amorphous lactose and β-lactose contents were increased. Thus, this study demonstrated that it is possible to prepare engineered lacrosse particles with favourable properties for DPI formulations using lactose solutions with a low degree of saturation during crystallization.
Delivery of two drugs in one dry powder inhaler (DPI) is expected to play an increasing and more ... more Delivery of two drugs in one dry powder inhaler (DPI) is expected to play an increasing and more effective role in the management of asthma and chronic obstructive pulmonary disease. In this study we investigated five sugars as possible carriers of both budesonide, an anti-inflammatory glucocorticoid, and formoterol, a long-acting β agonist, in one DPI formulation. Most DPI formulations utilise lactose as a carrier in the drug-carrier blends; however, it cannot be used for compounds that react with its reducing group, such as budesonide, formoterol, or peptide/proteinbased drugs. Therefore, alternative carriers such as sorbitol, mannitol, dextrose and xylitol were selected for this study in addition to lactose, which was used as a reference. A formulation comprising 5% w/w budesonide and 0.3% w/w formoterol was prepared with each sugar. The carriers were sieved to obtain 63-90 µm fractions and physicochemically characterised via true density, powder flow, particle size and surface morphology analyses. The dispersion and deaggregation of the two drugs from the five formulations were assessed after aerosolisation at 58-68 L min-1 via a device-metered Airmax inhaler into a Multi-Stage Liquid Impinger. The findings show that the deposition efficiencies of the five formulations were influenced by the particle size distribution, surface morphology and flowability of the respective carriers, and that mannitol showed the greatest potential as an alternative carrier to lactose. Mannitol produced the highest fine particle fraction values of 72.4% and 27.5% for budesonide and formoterol, respectively, and this performance was largely attributable to the relatively high percentage of fine particles (< 10.50 µm) compared to the other carriers.
Http Dx Doi Org 10 3109 10837450903002173, Jan 21, 2010
Ethylcellulose microparticles containing tolmetin sodium, an anti-inflammatory drug, were prepare... more Ethylcellulose microparticles containing tolmetin sodium, an anti-inflammatory drug, were prepared by a solvent diffusion method based on the formation of multiple W/O(1)/O(2)-emulsion. The drug used was TOL, which is water-soluble and n-hexane was used as the non-solvent. Important parameters in the evaluation of a microencapsulation technique are actual drug loading, the encapsulation efficiency, the yield, solvent systems, dispersed phase to continuous phase ratio (DP/CP ratio), composition of continuous phase, drug distribution in microparticles and stability of primary emulsion. A small volume of internal aqueous phase and volume of organic solvent were favorable to achieve high drug encapsulation efficiencies. Since drug release during the initial stages depends mostly on the diffusion escape of the drug, major approaches to prevent the initial burst have focused on efficient encapsulation of the drug within the microparticles. For this reason, control of efficiency and the extent of initial burst are based on common formulation parameters. Most parameters affect encapsulation efficiency and initial burst by modifying solidification rate of dispersed phase. In order to prevent many unfavorable events such as pore formation, drug loss, and drug migration that occur while the dispersed phase is in the semi-solid state, it is important to understand and optimize these variables.
The aim of this study was to evaluate microencapsulated controlled release preparations of tolmet... more The aim of this study was to evaluate microencapsulated controlled release preparations of tolmetin sodium using ethylcellulose as a retardant material. Microspheres were prepared by using water-in-oil-in-oil (W/O(1)/O(2)) double-emulsion solvent diffusion method, using different ratios of ethylcellulose to tolmetin sodium. Span 80 was used as the droplet stabilizer and n-hexane was added to harden the microspheres. The prepared microspheres were characterized for their micromeritic properties, drug content, loading efficiency, production yield, and particle size. Fourier transform infrared spectroscopy, differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy were used to characterize microparticles. The in vitro release studies were performed in pH 1.2 and 7.4. The prepared microspheres were spherical in shape. The drug-loaded microspheres showed near to the theoretical of entrapment and release was extended up to 24. The X-ray diffractogram and differential scanning thermographs showed amorphous state of the drug in the microspheres. It was shown that the drug: polymer ratio, stirring rate, volume of dispersing medium and surfactant influenced the drug loading, particle size and drug release behavior of the formed microparticles. The results showed that, generally, an increase in the ratio of drug: polymer (0.5:1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The in vitro release profile could be modified by changing various processing and formulation parameters to give a controlled release of drug from the microparticules. The release of tolmetin was influenced by the drug to polymer ratio and particle size and was found to be diffusion and erosion controlled. The best-fit release kinetic was achieved with Peppas model.
The purpose of this investigation was to evaluate microencapsulated controlled release preparatio... more The purpose of this investigation was to evaluate microencapsulated controlled release preparation of theophylline using Eudragit RS 100 as the retardant material with high entrapment efficiency. Microspheres were prepared by the emulsion-solvent evaporation method. A mixed solvent system consisting of methanol and acetone and light liquid paraffin as oily phase were chosen. Sucrose stearate was used as the surfactant to stabilize the emulsification process. The prepared microspheres were characterized by drug loading, Fourier-transform infrared spectroscopy (FTIR), differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The in vitro release studies were performed at pH 1.2 and 7.4 aqueous medium. Increasing the concentration of emulsifier, sucrose fatty acid ester F-70, decreased the particle size which contributed to increased drug release rate. The drug loading microparticle Eudragit RS100(1:6) showed 60-75% of entrapment and mean particle size 205.93-352.76 μm.The results showed that, an increase in the ratio of polymer: drug (F5, 6: 1) resulted in a reduction in the release rate of the drug which may be attributed to the hydrophobic nature of the polymer. The release of theophylline is influenced by the drug to polymer ratio and particle size. Drug release is controlled by diffusion and the best-fit release kinetic is Higuchi model.
Hard gelatin capsule was coated by a cellulose acetate as a semipermeable membrane with or withou... more Hard gelatin capsule was coated by a cellulose acetate as a semipermeable membrane with or without castor oil and filled with propranolol hydrochloride and sorbitol as an osmotic agent. After sealing the capsule with white bees wax plug, the onset of release and dissolution rate of the drug were studied. Water penetration into the capsule from the dissolution medium increases simultaneously the osmotic and hydrostatic pressures of its content. When the hydrostatic pressure is high enough to overweigh the gravity and frictional forces of the plug, the expulsion of the plug occurs and drug release starts. The effects of thicknesses of the membrane and plug as well as the concentrations of cellulose acetate and castor oil on the onset of drug release were presented by a polynomial model. We found that the effect of plug thickness on the onset of release is more important when the membrane is thicker. The results showed that the presence of caster oil in coating formulation (cellulose acetate 10% or 15%) increased the onset of release (t(o) values). The onset of release varied from 0.6 to 10.5 hr among which the onset times of 4.2, 4.8, 5.9, 5.5, 7.5, 5.0, 7.8 and 10.5 hr could be of use for either chronotherapeutic purposes in protection of patients against heart attacks and strokes during early morning hours or reducing daily frequency of dosage.
International Journal of Pharmaceutics, Feb 3, 2006
Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and ath... more Benzoyl peroxide (BPO) is commonly used in topical formulations for the treatment of acne and athletes foot. Skin irritation is a common side effect, and it has been shown that controlled release of BPO from a delivery system to the skin could reduce the side effect while reducing percutaneous absorption. Therefore, the aim of the present study was to produce ethylcellulose microparticles containing BPO which were able to control the release of BPO to the skin. In order to optimize the microparticle formulation, factors affecting the physical properties of microparticles were also investigated. Benzoyl peroxide microparticles were prepared using an emulsion solvent diffusion method by adding an organic internal phase containing benzoyl peroxide, ethyl cellulose and dichloromethane into a stirred aqueous phase containing polyvinyl alcohol. Drug content, particle size analysis and loading yield were determined in the prepared microparticles. BPO microparticles were then incorporated into standard vehicles for release studies. Scanning electron microscopy was used to study the shape and morphology of the microsponges. The micrograph of microsponges showed that they were spherical in shape and contained pores. These pores resulted from the diffusion of solvent from the surface of the microparticles and thus the particles were designated as microsponges. It was shown that the drug:polymer ratio, stirring rate, volume of dispersed phase influenced the particle size and drug release behavior of the formed microsponges and that the presence of emulsifier was essential for microsponge formation. The results showed that, generally, an increase in the ratio of drug:polymer resulted in a reduction in the release rate of BPO from microsponges which was attributed to a decreased internal porosity of the microsponges.
Http Dx Doi Org 10 3109 03639045 2014 991401, Dec 11, 2014
The cogrinding technique is one of most effective methods for improving the dissolution of poorly... more The cogrinding technique is one of most effective methods for improving the dissolution of poorly water soluble drugs and it is superior to other approaches from an economical as well as an environmental stand point, as the technique does not require any toxic organic solvents.
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