Modafinil-excipient compatibility study using differential scanning calorimetry.

Drug excipient compatibility studies are considered important in successful formulation of drug products. Suggested methods for this purpose are thermal techniques under isothermal or nonisothermal conditions. In this study, modafinil, a wakefulness-promoting drug, was investigated under nonisothermal conditions using differential scanning calorimetry. Four different heating rates, 5, 10, 15, and 20°C/min, were performed for modafinil pure material and its physical mixtures with magnesium stearate (MgSt) or Gelucire 48/16. Activation energy (Ea) was calculated from the straight line of plotting a function of heating rate versus temperature and found that modafinil-Gelucire physical mixture increased Ea. This indicates drug-excipient interaction, supported by evidence from Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. No significant interaction was detected with MgSt.

Investigating Variation in Compressional Behavior of a Ternary Mixture from a Plastic, Elastic and Brittle Fracture Perspective in the Context of Optimum Composition of a Pharmaceutical Blend.

The choice of optimum composition of a mixture of binary and ternary excipients for optimum compressional properties was investigated in this work. Excipients were chosen based on three types of excipients: plastic, elastic, and brittle fracture. Mixture compositions were selected based on a one-factor experimental design using the response surface methodology technique. Compressive properties comprising Heckel and Kawakita parameters, work of compression, and tablet hardness were measured as the main responses of this design. The one-factor RSM analysis revealed that there exist specific mass fractions that are associated with optimum responses for binary mixtures. Furthermore, the RSM analysis of the 'mixture' design type for the three components revealed a region of optimal responses around a specific composition. The foregoing had a mass ratio of 80:15:5 for microcrystalline cellulose: starch: magnesium silicate, respectively. Upon comparison using all RSM data, ternary mixtures were found to perform better in compression and tableting properties than binary mixtures. Finally, the finding of an optimal mixture composition has proven effective in its applicability in the context of the dissolution of model drugs (metronidazole and paracetamol).

Influence of Chitin Source and Polymorphism on Powder Compression and Compaction: Application in Drug Delivery.

The objective of the research reported herein is to compare the compaction properties of three different chitin extracts from the organisms most used in the seafood industry; namely crabs, shrimps and squids. The foregoing is examined in relation to their polymorphic forms as well as compression and compaction behavior. Chitin extracted from crabs and shrimps exhibits the α-polymorphic form whilst chitin extracted from squid pins displays a ß-polymorphic form. These polymorphs were characterized using FTIR, X-ray powder diffraction and scanning electron microscopy. Pore diameter and volume differ between the two polymorphic powder forms. The ß form is smaller in pore diameter and volume. Scanning electron microscopy of the two polymorphic forms shows clear variation in the arrangement of chitin layers such that the α form appears more condensed due to the anti-parallel arrangement of the polymer chains. True, bulk and tapped densities of these polymorphs and their mixtures indicated poor flowability. Nevertheless, compression and compaction properties obtained by applying Heckle and Kawakita analyses indicated that both polymorphs are able to be compacted with differences in the extent of compaction. Chitin compacts, regardless of their origin, showed a very high crushing strength with very fast dissolution which makes them suitable for use as fast mouth dissolving tablets. Moreover, when different chitin powders are granulated with two model drugs, i.e., metronidazole and spiramycin they yielded high crushing strength and their dissolution profiles were in accordance with compendial requirements. It is concluded that the source of chitin extraction is as important as the polymorphic form when compression and compaction of chitin powders is carried out.

Understanding the Performance of a Novel Direct Compression Excipient Comprising Roller Compacted Chitin.

Chitin has been investigated in the context of finding new excipients suitable for direct compression, when subjected to roller compaction. Ball milling was concurrently carried out to compare effects from different energy or stress-inducing techniques. Samples of chitin powders (raw, processed, dried and humidified) were compared for variations in morphology, X-ray diffraction patterns, densities, FT-IR, flowability, compressibility and compactibility. Results confirmed the suitability of roller compaction to convert the fluffy powder of raw chitin to a bulky material with improved flow. X-ray powder diffraction studies showed that, in contrast to the high decrease in crystallinity upon ball milling, roller compaction manifested a slight deformation in the crystal lattice. Moreover, the new excipient showed high resistance to compression, due to the high compactibility of the granules formed. This was correlated to the significant extent of plastic deformation compared to the raw and ball milled forms of chitin. On the other hand, drying and humidification of raw and processed materials presented no added value to the compressibility and compactibility of the directly compressed excipient. Finally, compacted chitin showed direct compression similarity with microcrystalline cellulose when formulated with metronidazole (200 mg) without affecting the immediate drug release action of the drug.

A Direct Compression Matrix Made from Xanthan Gum and Low Molecular Weight Chitosan Designed to Improve Compressibility in Controlled Release Tablets.

The subject of our research is the optimization of direct compression (DC), controlled release drug matrices comprising chitosan/xanthan gum. The foregoing is considered from two main perspectives; the use of low molecular weight chitosan (LCS) with xanthan gum (XG) and the determination of important attributes for direct compression of the mixtures of the two polymers. Powder flow, deformation behaviour, and work of compression parameters were used to characterize powder and tableting properties. Compression pressure and LCS content within the matrix were investigated for their influence on the crushing strength of the tablets produced. Response surface methodology (RSM) was applied to determine the optimum parameters required for DC of the matrices investigated. Results confirm the positive contribution of LCS in enhancing powder compressibility and crushing strength of the resultant compacts. Compactibility of the XG/LCS mixtures was found to be more sensitive to applied compression pressure than LCS content. LCS can be added at concentrations as low as 15% w/w to achieve hard compacts, as indicated by the RSM results. The introduction of the plasticity factor, using LCS, to the fragmenting material XG was the main reason for the high volume reduction and reduced porosity of the polymer mixture. Combinations of XG with other commonly utilized polymers in controlled release studies such as glucosamine, hydroxypropyl methylcellulose (HPMC), Na alginate (ALG), guar gum, lactose and high molecular weight (HMW) chitosan were also used; all the foregoing polymers failed to reduce the matrix porosity beyond a certain compression pressure. Application of the LCS/XG mixture, at its optimum composition, for the controlled release of two model drugs (metoprolol succinate and dyphylline) was examined. The XG/LCS matrix at 15% w/w LCS content was found to control the release of metoprolol succinate and dyphylline. The former preparation confirmed the strong influence of compression pressure on changing the drug release profile. The latter preparation showed the ability of XG/LCS to extend the drug release at a fixed rate for 12 h of dissolution time after which the release became slightly slower.

Preparation and characterization of co-processed starch/MCC/chitin hydrophilic polymers onto magnesium silicate.

It was aimed to investigate the compressibility, compactibility, powder flow and tablet disintegration of a new excipient comprising magnesium (Mg) silicate co-processed (5%-85% w/w) onto chitin, microcrystalline cellulose (MCC) and starch as the hydrophilic polymers of interest. Initially, the mechanism of tablet disintegration was studied by measuring water infiltration rate, moisture sorption, swelling capacity and hydration ability. Moreover, the powders compression behavior was carried out by applying Kawakita model of compression analysis in addition to porosity and radial tensile strength measurements. In vitro drug release of compacts made of 400 mg ibuprofen and 300 mg of the hydrophilic polymers containing 30% w/w Mg silicate co-precipitate was investigated in phosphate buffer (pH 7.8). This work demonstrated that the incorporation of Mg silicate to the hydrophilic polymers lead to the improvement of powder flowability, compactibility, stability (with regard to storage conditions), compacts crushing strength, and disintegration time in addition to faster drug release. The overall findings are practically advantageous in the context of finding a low cost and multifunctional co-processed excipient of natural origins.

Modification of α-lactose monohydrate as a direct compression excipient using roller compaction.

Roller compaction was used to prepare a direct-compressed lactose excipient using crystalline α-lactose monohydrate. The effect of various roller compaction process parameters (compaction pressure, compaction repetition, and speed ratio) on the characteristics of compacted α-lactose monohydrate was investigated. Results were compared with data obtained using industrial spray-dried lactose and lactose samples with different degrees of crystallinity. XRPD analysis revealed that roller compaction reduced the crystallinity of α-lactose monohydrate, and the resulting material is similar to spray-dried lactose in behavior as a direct compression excipient. Roller compaction introduced desirable characteristics to the raw α-lactose monohydrate by inducing changes in crystallinity and particle morphology. Scanning electron microscopy results indicated that the compaction process converted some of the original torpedo-shaped crystals of α-lactose monohydrate into a more cylindrical shape with rounded edges. Compaction pressure and repetition of compaction have a significant effect on the modification of the crystallinity of the processed, raw α-lactose monohydrate.

Prasugrel Hydrochloride.

A comprehensive profile of prasugrel HCl is reported herein with 158 references. A full description including nomenclature, formulae, elemental analysis, and appearance is included. Methods of preparation for prasugrel HCl, its intermediates, and derivatives are fully discussed. In addition, the physical properties, analytical methods, stability, uses and applications, and pharmacology of prasugrel HCl are also discussed.

Chitin and chitosan as direct compression excipients in pharmaceutical applications.

Despite the numerous uses of chitin and chitosan as new functional materials of high potential in various fields, they are still behind several directly compressible excipients already dominating pharmaceutical applications. There are, however, new attempts to exploit chitin and chitosan in co-processing techniques that provide a product with potential to act as a direct compression (DC) excipient. This review outlines the compression properties of chitin and chitosan in the context of DC pharmaceutical applications.

Formulation and in vitro assessment of sustained release terbutaline sulfate tablet made from binary hydrophilic polymer mixtures.

In the present systematic study, a sustained release of terbutaline sulfate tablet (TBS) was developed and optimized by employing the hydrophilic polymers; chitosan and xanthan gum mixed with sodium bicarbonate as a release modifying agent. This formulation was developed using direct compression technology. In vitro release studies indicated rapid swelling and drug release in the initial period of the acid stage from a matrix composed of chitosan and xanthan gum solely. Addition of sodium bicarbonate to the matrix resulted in sustained drug release. Various formulation factors such as polymer to polymer ratio, polymer viscosity and particle size were altered and their effect on dissolution pattern was illustrated. Manufacturing variables such as compression force and lubricant percentage were investigated and found not to influence the drug release profile of the resulted tablets. The release mechanism follows Korsmeyer-Peppas equation with n value indicating non-Fickian diffusion. The release profiles were analyzed using statistical method (one-way ANOVA) and f2 metric values and found to be similar to the commercial product Bricanyl(®). Reproducible data were obtained when scale-up of the formulation was performed.

Determination of solid-state acidity of chitin-metal silicates and their effect on the degradation of cephalosporin antibiotics.

It was of interest to determine the solid-state acidity of chitin-metal silicate coprocessed excipients and to correlate this acidity to the chemical stability of cefotaxime sodium in the presence of the aforementioned excipients. The solid-state acidities of chitin aluminum silicate, chitin magnesium silicate, and chitin calcium silicate were determined by reflectance spectroscopy using structurally different dye molecules. The chemical stability of cefotaxime sodium was assessed at 50 °C in a 4% (w/v) slurry system in the pH range 6.6-10.5 and in the solid-state in the Hammett acidity range 6.1-7.8. The solid-state acidity was found to be reproducible because one or more structurally different dye molecules gave reliable solid-state acidity values. A significant discrepancy in pH stability profile of cefotaxime sodium between the solid-state and the slurry system was observed. Furthermore, chitin aluminum silicate showed minimum drug stability in the solid-state, close to where the maximum drug stability in the slurry was observed. This unexpected effect might be ascribed to the catalytic properties of chitin aluminum silicate. The slurry method was not able to predict efficiently the solid-state surface acidity and stability of cefotaxime sodium. Moreover, the solid-state chemical stability might be influenced by factors other than the solid-state acidity.

A novel multifunctional pharmaceutical excipient: modification of the permeability of starch by processing with magnesium silicate.

A directly compressible excipient has been developed by co-processing starch with magnesium silicate. The foregoing was achieved either by co-precipitation of magnesium silicate onto different types of starch or by dry granulation of maize starch with magnesium silicate. A variety of techniques (permeability, water retention/swelling, compression analysis, scanning electron microscopy, tensile strength and disintegration/dissolution studies) were used to characterize these systems. The permeability of the formulations produced using the two methods was evaluated experimentally using Darcy's permeability law. Magnesium silicate, as an anti-adhering agent, increases the permeability of both maize and partially pregelatinized starch, resulting in compacts of high mechanical strength, short disintegration time and low lubricant sensitivity. Such advantages are evident when the properties of the physical mixture of maize starch with magnesium silicate are compared with the co-precipitation and dry granulation techniques. Formulation with this novel excipient system, using paracetamol as a model drug, indicated its suitability as a single multifunctional excipient.

Magnesium silicate.

A comprehensive profile of magnesium silicate with 80 references is reported. A full description including nomenclature, formulae, and appearance is included. Methods for magnesium silicate preparation including precipitation, hydrothermal precipitation, and mechanochemical dehydration are reviewed. Physical characteristics, compendia and non-compendia analytical methods, uses, stability and incompatibilities, biodegradability, toxicity, and substances related to magnesium silicate are also discussed.

Preparation and characterization of a novel co-processed excipient of chitin and crystalline mannitol.

A co-processed excipient was prepared from commercially available crystalline mannitol and α-chitin using direct compression as well as spray, wet, and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size, on the properties of the prepared co-processed excipient has been investigated. α-Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol-chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol-chitin (2:8, w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength, and friability of tablets, produced from Cop-MC using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, high-strength, and low-strength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient.

Evaluation of three chitin metal silicate co-precipitates as a potential multifunctional single excipient in tablet formulations.

The performance of the novel chitin metal silicate (CMS) co-precipitates as a single multifunctional excipient in tablet formulation using direct compression and wet granulation methods is evaluated. The neutral, acidic, and basic drugs Spironolactone (SPL), ibuprofen (IBU) and metronidazole (MET), respectively, were used as model drugs. Commercial Aldactone, Fleximex and Dumazole tablets containing SPL, IBU and MET, respectively, and tablets made using Avicel 200, were used in the study for comparison purposes. Tablets of acceptable crushing strength (>40 N) were obtained using CMS. The friability values for all tablets were well below the maximum 1% USP tolerance limit. CMS produced superdisintegrating tablets (disintegration time < 1 min) with the three model drugs. Regarding the dissolution rate, the sequence was as follow: CMS > Fleximex > Avicel 200, CMS > Avicel 200 > Dumazole and Aldactone > Avicel 200 > CMS for IBU, MET and SPL, respectively. Compressional properties of formulations were analyzed using density measurements and the compression Kawakita equation as assessment parameters. On the basis of DSC results, CMS co precipitates were found to be compatible with the tested drugs. Conclusively, the CMS co-precipitates have the potential to be used as filler, binder, and superdisintegrant, all-in-one, in the design of tablets by the direct compression as well as wet granulation methods.

Bioadhesive controlled metronidazole release matrix based on chitosan and xanthan gum.

Metronidazole, a common antibacterial drug, was incorporated into a hydrophilic polymer matrix composed of chitosan xanthan gum mixture. Hydrogel formation of this binary chitosan-xanthan gum combination was tested for its ability to control the release of metronidazole as a drug model. This preparation (MZ-CR) was characterized by in vitro, ex vivo bioadhesion and in vivo bioavailability study. For comparison purposes a commercial extended release formulation of metronidazole (CMZ) was used as a reference. The in vitro drug-release profiles of metronidazole preparation and CMZ were similar in 0.1 M HCl and phosphate buffer pH 6.8. Moreover, metronidazole preparation and CMZ showed a similar detachment force to sheep stomach mucosa, while the bioadhesion of the metronidazole preparation was higher three times than CMZ to sheep duodenum. The results of in vivo study indicated that the absorption of metronidazole from the preparation was faster than that of CMZ. Also, MZ-CR leads to higher metronidazole C(max) and AUC relative to that of the CMZ. This increase in bioavailability might be explained by the bioadhesion of the preparation at the upper part of the small intestine that could result in an increase in the overall intestinal transit time. As a conclusion, formulating chitosan-xanthan gum mixture as a hydrophilic polymer matrix resulted in a superior pharmacokinetic parameters translated by better rate and extent of absorption of metronidazole.

Characterization of chitin-metal silicates as binding superdisintegrants.

When chitin is used in pharmaceutical formulations, processing of chitin with metal silicates is advantageous, from both an industrial and pharmaceutical perspective, compared to processing using silicon dioxide. Unlike the use of acidic and basic reagents for the industrial preparation of chitin-silica particles, coprecipitation of metal silicates is dependent upon a simple replacement reaction between sodium silicate and metal chlorides. When coprecipitated onto chitin particles, aluminum, magnesium, or calcium silicates result in nonhygroscopic, highly compactable/disintegrable compacts. Disintegration and hardness parameters for coprocessed chitin compacts were investigated and found to be independent of the particle size. Capillary action appears to be the major contributor to both water uptake and the driving force for disintegration of compacts. The good compaction and compression properties shown by the chitin-metal silicates were found to be strongly dependent upon the type of metal silicate coprecipitated onto chitin. In addition, the inherent binding and disintegration abilities of chitin-metal silicates are useful in pharmaceutical applications when poorly compressible and/or highly nonpolar drugs need to be formulated.

A novel superdisintegrating agent made from physically modified chitosan with silicon dioxide.

Disintegrants and fillers represent important excipients for immediate-release solid dosage forms in many pharmaceutical applications. A new excipient based on the coprecipitation of chitosan and silica has been achieved. The "intimate" physical association between chitosan and silica creates an insoluble, hydrophilic, highly absorbent material, consequently, resulting in superiority in water uptake, water saturation for gelling formation, and compactability among other superdisintegrants. The new excipient has an outstanding functionality that does not primarily depend on water wicking and swelling properties. In fact, it translates it into superior disintegration characteristics with improved powder flow and compaction properties. Thus, the new excipient could act as a superdisintegrant and pharmaceutical filler at the same time. Studies have shown that chitosan-silica delivers superior performance in wet granulation formulations and is the only disintegrant that is effective at all concentrations in tablet formulation.

Chitin-silicon dioxide coprecipitate as a novel superdisintegrant.

Chitin-silica represents a potentially useful superdisintegrant in many pharmaceutical applications. The "intimate" association between chitin and silica, without evidence of chemical reaction, creates an insoluble, hydrophilic, highly absorbent inert material. The new superdisintegrant is characterized by superiority in water uptake and water penetration, with no gelling hindrance effects, as well as compatibility with pharmaceutical drugs. In addition, it has an outstanding functionality that does not depend on swelling properties, as in the case of most conventional superdisintegrants. Chitin-silica offers good compressibility and compactability characteristics that may allow it to function as a pharmaceutical filler. Studies have shown that chitin-silica, as a superdisintegrant, is effective at all concentrations tested in tablet formulation.