Use of Dicalcium Phosphate Dihydrate for Sustained Release of Highly Water Soluble Drugs

The utilituy of Dicalcium phosphate dihydrate (DCPD), a commonly used water insoluble pharmaceutical excipient, has been investigated for its use in formulating a controlled release matrix type tablet for highly water soluble drugs. Various drugs were formulated into a tablet by direcly compressing mixture of the drug, dicalcium phosphate dihydrate, and magnecium stearate on a single punch tablet machine. Effects of drug concentation and tablet weight on the release profiles were studied using USP II dissolution machine.

The release from these matrices followed first order kinetics rather than square root time rule. The release profile and the first order rate constant seemed to be dependent upon the the size of the tablet. Incorporation of drug in a quantity excess of 5% w/w of the tablet resulted in disintegration of the tablet and subsequent rapid release of the drug.

Dicalcium phosphate may be a simpler, cheaper, and a viable way to formulating directly compressible sustained release formulations.     

Matrix Type Tablet Formulation for Controlled Release of Highly Water Soluble Drugs

Matrix type formulations with dicalcium phosphate dihydrate (DCPD) using a polymeric binder (Eudragit RSPM®) to obtain controlled release of highly water soluble drugs has been investigated.

The drug, DCPD and Eudragit RSPM® were granulated using isopropyl alcohol with and without a plasticizer (Diethyl phthalate, DEP). Addition of Eudragit did not appear to affect the release profile. However, addition of a plasticizer had a significant effect on the rate of release. The release appears to follow first order kinetics and the rate constant decreased linearly with increasing DEP concentration.

A directly compressible mixture was also formulated by coating DCPD particles with DEP with and without Eudragit RSPM®.     

An Examination of Assumptions Underlying the First-Order Kinetic Model for Release of Water-Soluble Drugs from Dicalcium Phosphate Dihydrate Matrices

Abstract

It has been shown that the release of highly water-soluble drugs from compressed dicalcium phosphate dihydrate matrices follows first-order kinetics (1). Good correlation between the rate constant and tablet geometry (2) was also reported. However, the rate constants for different geometry could not be predicted accurately by using the constants obtained for cylindrical tablets. In this work the assumptions regarding the surface area, porosity, and inertness of the drug toward the matrix have been tested using simple experimental designs and techniques such as porosimetry, electron microscopy, and differential scanning calorimetry. No interactions between the drug and the matrix were observed. The assumptions regarding porosity/void volume seemed to hold. Using water as a penetrant gave better estimate of porosities than those obtained using mercury. The assumption regarding surface area needs correction; however, a better alternative has not been proposed.     

The swelling of core tablets during aqueous coating II: An application of the model describing extent of swelling and water penetration for insoluble tablets

Abstract

A mathematical model successfully describing the extent of swelling and water penetration for dicalcium phosphate dihydrate(Ditab) tablets is able to be applied to the anhydrous form. The extent of swelling/water penetration behavior exhibited by anhydrous dicalcium phosphate(ATAB) is quite different from that of dihydrate form, which exhibits non-swelling. More water tends to penetrate into ATAB tablets than those tablets prepared from Ditab. The water uptake is coincident to the very large surface tablet porosity.     

A Comparison of Trehalose Dihydrate and Mannitol as Stabilizing Agents for Dicalcium Phosphate Dihydrate Based Tablets

This study investigated the possible utility of trehalose dihydrate (TD) as a tablet stabilizing agent. Acetylsalicylic acid was used as the model hydrolyzable drug and dicalcium phosphate dihydrate (DCPD) as the base excipient, because it is well documented that ASA/DCPD tablets are unstable during storage at low temperature and high relative humidity; DCPD is usually combined with mannitol in order to improve tablet stability.

Tablets comprising DCPD, 10% ASA, and 0%, 10%, or 20% w/w of TD were prepared by direct compression and stored at 35°C and 82.9% relative humidity for 6 months. Additionally, control tablets with DCPD and ASA, only, or with DCPD, ASA and 20% mannitol, were also evaluated. At predetermined time intervals, formulations were tested for drug content, mechanical, microstructural, and drug dissolution properties. Additionally, thermal analyses and ASA solution stability studies were carried out. Results reveal that both TD and mannitol significantly reduce degradation of ASA included in DCPD-based tablets, but neither effectively protects against the marked decline in tablet mechanical properties on aging. The ASA stabilization effects of TD and mannitol were also observed in solution, indicating an interaction between these sugars and ASA.     

A New Computer-Aided Apparatus for Simultaneous Measurements of Water Uptake and Swelling Force in Tablets

Abstract

Water uptake and disintegrating force development have frequently been related to tablet disintegration properties.

Water penetration into compressed tablets has been studied by many authors using modified Enslin apparatus. Meanwhile, in previous papers by our group, a great deal of attention has been paid to the measurements of disintegrating force and to the kinetics of force development.

Given the fact that water penetration and swelling force development are related to each other, a new apparatus was set up which allows simultaneous measurements of water penetration and force development. It consists of a modified apparatus for force measurements, integrated with a modified Enslin apparatus. Both force and water uptake data were collected by a computer and stored for subsequent analysis.

Fitting of both water penetration and force development curves was performed with a commercially available software package for non-linear regression analysis.

This enables an examination of the relationships between force development and water penetration on the basis of homogeneous rate parameters. The apparatus was validated on a model tablet formulation based on dicalcium phosphate dihydrate with carboxymethylstarch.

Besides application in fast disintegrating tablets, this approach could be useful to study the behaviour of swelling-controlled release systems, in which the release mechanism (swelling force) is triggered by water penetration.     

Fabrication and in vitro evaluation of bidirectional release and stability studies of mucoadhesive donut-shaped captopril tablets

Objective: To obtain controlled release of captopril in the stomach, coated, mucoadhesive donut-shaped tablets were designed.

Materials and methods: Donut-shaped tablet were made of different ratios of diluents to polymer or combination of polymers by direct compression method. Top and bottom portions of the tablet were coated with water-insoluble polymer followed by mucoadhesive coating. Time of water penetration, measurement of tensile strength, mucoadhesion studies (static ex vivo and ex vivo wash-off) were taken into account for characterization of respective films. In vitro study has been performed at different dissolution mediums. Optimized batches were also prepared by wet granulation. Stability studies of optimized batches have been performed.

Results: The results of time of water penetration and tensile strength indicated positive response against water impermeation. Mucoadhesive studies showed that film thickness of 0.12?mm was good for retention of tablet at stomach. At pH 1.2, optimized batch of tablet made with hydroxypropyl methyl cellulose (HPMC) E15 as binder showed 80% w/w drug release within 4–5?h with maximum average release of 97.49% w/w. Similarly, maximum average releases of 96.36% w/w and 95.47% w/w were obtained with nearly same dissolution patterns using combination of HPMC E5 and HPMC E50 and sodium salt of carboxy methyl cellulose (NaCMC) 500–600 cPs instead of HPMC E15. The release profiles in the distilled water and pH 4.5 followed the above pattern except deviation at pH 6.8. Stability studies were not positive for all combinations.

Conclusion: Coated, mucoadhesive donut-shaped tablet is good for controlled release of drug in the stomach.     

The influence of HPMC concentration on release of theophylline or hydrocortisone from extended release mini-tablets

Context: Mini-tablets are compact dosage forms, typically 2–3 mm in diameter, which have potential advantages for paediatric drug delivery. Extended release (ER) oral dosage forms are intended to release drugs continuously at rates that are sufficiently controlled to provide periods of prolonged therapeutic action following each administration, and polymers such as hypromelllose (HPMC) are commonly used to produce ER hydrophilic matrices.

Objective: To develop ER mini-tablets of different sizes for paediatric delivery and to study the effects of HPMC concentration, tablet diameter and drug solubility on release rate.

Methods: The solubility of Hydrocortisone and theophylline was determined. Mini-tablets (2 and 3 mm) and tablets (4 and 7 mm) comprising theophylline or hydrocortisone and HPMC (METHOCEL? K15M) at different concentrations (30, 40, 50 and 60%w/w) were formulated. The effect of tablet size, HPMC concentration and drug solubility on release rate and tensile strength was studied.

Results and Discussion: Increasing the HPMC content and tablet diameter resulted in a significant decrease in drug release rate from ER mini-tablets. In addition, tablets and mini-tablets containing theophylline produced faster drug dissolution than those containing hydrocortisone, illustrating the influence of drug solubility on release from ER matrices. The results indicate that different drug release profiles and doses can be obtained by varying the polymer content and mini-tablet diameter, thus allowing dose flexibility to suit paediatric requirements.

Conclusion: This work has demonstrated the feasibility of producing ER mini-tablets to sustain drug release rate, thus allowing dose flexibility for paediatric patients. Drug release rate may be tailored by altering the mini-tablet size or the level of HPMC, without compromising tablet strength.     

Compatibility Study Between Atenolol and Tablet Excipients Using Differential Scanning Calorimetry

Abstract

In order to improve the formulation of atenolol the physico-chemical compatibility between the drug and various excipients, commonly used in tablet manufacturing, was studied with the aid of Differential Scanning Calorimetry (DSC).

Using this method, it was found that atenolol is compatible with starch, Sta-Rx®, Primojel®, Avicel PH®, Ac-Di-Sol®, cross-linked PVP, magnesium stearate, calcium sulphate dihydrate, dicalcium phosphate and icing sugar. Interactions of atenolol with PVP, lactose and the lubricant stearic acid were found, although it cannot be conlusively stated that interaction incompatibilities will occur during storage at room temperature.     

The Swelling of Core Tablets During Aqueous Coating I: A Simple Model Describing Extent of Swelling and Water Penetration for Insoluble Tablets Containing a Superdisintegrant

Abstract

A simple mathematical model was established to describe changes of tablet thickness due to swelling and water penetration during aqueous coating process. The model was illustrated by a simple linear equation, i.e.; D = -(α/(l+ε))l₁,+(α/(l+ε))l₀; where D, l₀,1₁, α and ε are the depth of water penetrating into tablets, initial tablet thickness, the remaining dried core tablet thickness, swelling and porosity parameters, respectively. The data from dicalcium phosphate dihydrate(Ditab) tablets containing a super-disintegrant may be fitted into the model showing significant statistical correlation. The model was valid for describing the extent of tablet swelling and water penetration during aqueous coating.     

Oral sustained release dosage forms comparison between matrices and reservoir devices

Abstract

For the formulation of a monolithic controlled release form for oral use, containing 80 mg of a highly soluble drug, different systems have been compared.

At first, matrices where prepared containing 37.3 percent of a water soluble polymer: HPMC (Methocel or Metolose) and HEC (Natrosol). With such swelling agents, it is quite difficult to reach a zero order release. But industrial scale-up is easy, because the process uses only classical machines. Variations intra and between batches have been found very small and stability is good.

An other possibility is a lipophilic matrix. Hard gelatin capsules were filled with a drug dispersion in Gélucire of different grades. The fabrication process is quite easy but at this time, few informations about stability are available.

A third convenient way is a reservoir device, a tablet coated with an insoluble polymer film (Aquacoat ECD 30). A zero order release was obtained until 80 percent of drug released after 12 hours. But the coating is a very critical phase of the process: disturbances affect the drug dissolution rate. The film may also be altered by the patient, who can break or crunch the tablet. In this case, all the drug is dissolved quasi instantaneously.

For all these reasons, the hydrophilic matrix was preferred, especially if a zero order is obtained.     

Water Uptake and Disintegrating Force Measurements: Towards a General Understanding of Disintegration Mechanisms

Water penetration and disintegrating force measurements were combined with the aim of assessing the role played by various mechanisms in the disintegration process.

Nine tablet series, made of differing base materials (α-lactose monohydrate, dicalcium phosphate dihydrate and acetylsalicylic acid) such as are likely to elicit differing disintegration mechanisms and containing differing disintegrates in varying percentages were prepared and checked for Water penetration, disintegrating force development and disintegration time.

The results obtained show that, in tablets made of dicalcium phosphate dihydrate or acetylsalicylic acid, a correlation exists between disintegration time and disintegrating force kinetics, which indicates that active mechanisms play the prevailing role in the disintegration process.

On the contrary, the lack of such a correlation in lactose monohydrate tablets indicates that passive mechanisms are also involved in the disintegration process and prevail over active mechanisms. In this case, water penetration rate, rather than disintegrating force development rate, seems to be the governing factor in the disintegration process.     

Formulation development and in vitro evaluation of solidified self-microemulsion in the form of tablet containing atorvastatin calcium

Aim: The objective of our present study was to prepare solid self-microemulsion in the form of tablet of a poorly water soluble drug, Atorvastatin calcium (ATNC) to increase the solubility, dissolution rate, and minimize the hazards experienced from liquid emulsions.

Materials and methods: Self-microemulsifying ATNC tablet was formulated mainly by using self-emulsifying base, solidifying agent silicon dioxide and sodium starch glycolate as tablet disintegrant. Self-emulsifying base containing Transcutol P, Gelucire 44/14, and Lutrol F68 with their ratios in the formulation, were best selected by solubility study and ternary phase diagram in different vehicles. Particle size of microemulsion from tablet, physical parameters of the tablet and drug content has been checked. In vitro drug release rate has been carried out in phosphate buffer medium (pH 6.8). Physicochemical characterization of the drug in the optimized formulation has been performed to check drug-excipient incompatibility, if any.

Results: Average particle diameter of the emulsions formed from the tablet was found to be below 100?nm in case of formulation F4 and F5, which indicated microemulsions has been formed. In vitro drug release from the formulations F3, F4, and F5 was found to be >90%, indicated the enhancement of solubility of ATNC compared to parent drug. Differential thermal analysis (DTA), Powder X-ray Diffraction (X-RD) and Fourier transform infra red (FTIR) study proved the identity of the drug in the optimized formulation.

Conclusion: The tablet form of self-microemulsifying (SME) drug delivery is good for solubility enhancement.     

An Examination of Assumptions Underlying the First-Order Kinetic Model for Release of Water-Soluble Drugs from Dicalcium Phosphate Dihydrate Matrices

It has been shown that the release of highly water-soluble drugs from compressed dicalcium phosphate dihydrate matrices follows first-order kinetics (1). Good correlation between the rate constant and tablet geometry (2) was also reported. However, the rate constants for different geometry could not be predicted accurately by using the constants obtained for cylindrical tablets. In this work the assumptions regarding the surface area, porosity, and inertness of the drug toward the matrix have been tested using simple experimental designs and techniques such as porosimetry, electron microscopy, and differential scanning calorimetry. No interactions between the drug and the matrix were observed. The assumptions regarding porosity/void volume seemed to hold. Using water as a penetrant gave better estimate of porosities than those obtained using mercury. The assumption regarding surface area needs correction; however, a better alternative has not been proposed.     

Matrix Type Tablet Formulation for Controlled Release of Highly Water Soluble Drugs

Matrix type formulations with dicalcium phosphate dihydrate (DCPD) using a polymeric binder (Eudragit RSPM®) to obtain controlled release of highly water soluble drugs has been investigated.

The drug, DCPD and Eudragit RSPM® were granulated using isopropyl alcohol with and without a plasticizer (Diethyl phthalate, DEP). Addition of Eudragit did not appear to affect the release profile. However, addition of a plasticizer had a significant effect on the rate of release. The release appears to follow first order kinetics and the rate constant decreased linearly with increasing DEP concentration.

A directly compressible mixture was also formulated by coating DCPD particles with DEP with and without Eudragit RSPM®.     

Development and In-Vitro Characterization of Sustained-Release Acetaminophen Tablets

Abstract

The objective of this study was to evaluate powdered lipids as both granulating agents and retardants in formulated sustained-release acetaminophen tablets. Castor Wax or Durkee 07 powders were premixed with acetaminophen and granulated with boiling water. After cooling, the mass was screened to obtain a 10/20 mesh fraction which was used for tablet production and evaluation. Friability, hardness, dissolution and compression profiles were monitored. As lipid content increased from 5-15% w/w, friability and hardness also increased. Dissolution showed an inverse relationship between level of lipid and release rate. Compression profiles demonstrated good transmission when Castor Wax was employed. This study demonstrated that a high milligram potency tablet could be fabricated with low levels of lipid, to retard drug release, without significantly increasing tablet weight and size.     

Matrix forming capabilities of three calcium diluents

Abstract

The formulation of drug substances with excipients capable of forming a matrix structure is an approach which has been successfully applied to sustain medicament release following oral administration. Investigations of materials which possess matrix forming properties have been limited to a few polymeric substances such as polyvinyl chloride, polyethylene, acrylic copolymers, and cellulose derivatives ^1-5 Calcium sulfate dihydrate, dibasic calcium phosphate dihydrate, and tribasic calcium phosphate have previously been used as fillers/diluents in the formulation of solid dosage forms. All three diluents exhibit poor solubility in media of pH 1.1 and are practically insoluble in media of pH 4.0 to 7.5. In addition, when blended with one of three drug candidates and compressed these materials sustain drug release via a matrix diffusional process at higher pH corresponding to that of the human intestine. These findings led to an investigation of these calcium diluents as matrix forming agents in sustained release solid dosage forms.     

Sustained-release from Layered Matrix System Comprising Chitosan and Xanthan Gum

ABSTRACT

Sustained-release tablets of propranolol HCl were prepared by direct compression using chitosan and xanthan gum as matrix materials. The effective prolongation of drug release in acidic environment was achieved for matrix containing chitosan together with xanthan gum which prolonged the drug release more extensive than that containing single polymer. Increasing lactose into matrix could adjust the drug release characteristic by enhancing the drug released. Component containing chitosan and xanthan gum at ratio 1:1 and lactose 75% w/w was selected for preparing the layered matrix by tabletting. Increasing the amount of matrix in barrier or in middle layer resulted in prolongation of drug release. From the investigation of drug release from one planar surface, the lag time for drug release through barrier layer was apparently longer as the amount of barrier was enhanced. Least square fitting the experimental dissolution data to the mathematical expressions (power law, first order, Higuchi's and zero order) was performed to study the drug release mechanism. Layering with polymeric matrix could prolong the drug release and could shift the release pattern approach to zero order. The drug release from chitosan-xanthan gum three-layer tablet was pH dependent due to the difference in charge density in different environmental pH. FT-IR and DSC studies exhibited the charge interaction between of NH₃⁺ of chitosan molecule and COO^? of acetate or pyruvate groups of xanthan gum molecule. The SEM images revealed the formation of the loose membranous but porous film that was due to the gel layer formed by the polymer relaxation upon absorption of dissolution medium. The decreased rate of polymer dissolution resulting from the decreased rate of solvent penetration was accompanied by a decrease in drug diffusion due to ionic interaction between chitosan and xanthan gum. This was suggested that the utilization of chitosan and xanthan gum could give rise to layered matrix tablet exhibiting sustained drug release.     

Effect of Particle Size and Excipients on the Dissolution Rate of Metronidazole from Solid Dosage Forms: II

Abstract

In-vitro dissolution tests were carried out with tablets prepared from different particle size ranges of metronidazole. Influence of tablet binding agents (Methylcellulose, polyvinyl pyrrolidone - (PVP), potato starch and gelatin) on the drug release were investigated under similar conditions. Comprimates containing PVP and drug with particle size 1.75 μm (in lactose mixture) gave optimum results. These findings may open new ways of formulating a metronidazole tablet exhibiting improved drug - liberation, subsequently with a better bioavailability than the KUON^R-Tablet manufactured in Hungary.     

A New Ibuprofen Pulsed Release Oral Dosage Form

Abstract

Drug constant release is not always the desired solution for controlled drug administration; some therapeutic situations require consecutive pulses of active principle

A biphasic oral delivery system able to release an immediate dose of therapeutic agent as well as a further pulse of drug after some hours could be interesting

In order to obtain such desired releasing performances, a new system (three layer tablet) has been designed with the following characteristics

- an energy source, able to deliver the two divided doses of drug

- a control element, between the drug layers, able to delay the release of the second dose of drug. This control element acts as a barrier and is made with a mixture of water swellable polymers

- an outer film, which is made of water impermeable polymer, that covers the second dose of drug and the barrier

The new system works through subsequent interactions with aqueous fluids of the three different layers of material in the following order

1 - rapid interaction of the uncoated part of the system, and immediate disintegration of the first dose;

2 - slow interaction of the barrier and its gelation;

3 - interaction of the second drug layer and development of a force able to break the barrier thus promoting the release of the second dose of drug. Preliminary in vivo experiments carried out on this biphasic pulsed release device containing Ibuprofen as a model drug, show two distinct peaks in plasma profiles thus indicating that the in vitro results are in good agreement with the in vivo blood levels