Anhydrous Dibasic Calcium Phosphate Research Articles

Biomimetic non-collagenous proteins-calcium phosphate complex with superior osteogenesis via regulating macrophage IL-27 secretion

Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration.

Excipient-Induced Lattice Disorder inActive Pharmaceutical Ingredient: Implications on Drug Product Continuous Manufacturing.

Our previous work (Mol Pharm, 20 (2023) 3427) showed that crystalline excipients, specifically anhydrous dibasic calcium phosphate (DCPA), facilitated the dehydration of carbamazepine dihydrate (CBZDH) and the formation of an amorphous product phase during the mixing stage of continuous tablet manufacturing. Understanding the mechanism of this excipient-induced effect was the object of this study. Blending with DCPA for 15 min caused pronounced lattice disorder in CBZDH. This was evident from the 190% increase in the apparent lattice strain determined by the Williamson-Hall plot. The rapid dehydration was attributed to the increased reactivity of CBZDH caused by this lattice disorder. Lattice disorder in CBZDH was induced by a second method, cryomilling it with DCPA. The dehydration was accelerated in the milled sample. Annealing the cryomilled sample reversed the effect, thus confirming the effect of lattice disorder on the dehydration kinetics. The hardness of DCPA appeared to be responsible for the disordering effect. DCPA exhibited a similar effect in other hydrates, thereby revealing that the effect was not unique to CBZDH. However, its magnitude varied on a case-by-case basis. The high shear powder mixing was necessary for rapid and efficient powder mixing during continuous drug product manufacturing. The mechanical stress imposed on the CBZDH, and exacerbated by DCPA, caused this unexpected destabilization.

Drug Phase Transformation and Water Redistribution during Continuous Tablet Manufacturing: A Case Study of Carbamazepine Dihydrate.

In recent years, continuous tablet manufacturing technology has been used to obtain regulatory approval of several new drug products. While a significant fraction of active pharmaceutical ingredients exists as hydrates (wherein water is incorporated stoichiometrically in the crystal lattice), the impact of processing conditions and formulation composition on the dehydration behavior of hydrates during continuous manufacturing has not been investigated. Using powder X-ray diffractometry, we monitored the dehydration kinetics of carbamazepine dihydrate in formulations containing dibasic calcium phosphate, anhydrous (DCPA), mannitol, or microcrystalline cellulose. The combined effect of nitrogen flow and vigorous mixing during the continuous mixing stage of tablet manufacture facilitated API dehydration. Dehydration was rapid and most pronounced in the presence of DCPA. The dehydration product, amorphous anhydrous carbamazepine, sorbed a significant fraction of the water released by dehydration. Thus, the dehydration process resulted in a redistribution of water in the powder blend. The unintended formation of an amorphous dehydrated phase, which tends to be much more reactive than its crystalline counterparts, is of concern and warrants further investigation.

Synthesis of Submicrometric Chitosan Particles Loaded with Calcium Phosphate for Biomedical Applications.

Chitosan particles loaded with dibasic calcium phosphate anhydrous (DCPA) is a promising strategy for combining antimicrobial and osteoconduction properties in regenerative medicine. However, mostly micrometer-sized particles have been reported in the literature, limiting their use and reducing their effect in the biomedical field. We have recently overcome this limitation by developing submicrometer-sized particles with electrospray technique. The objective of this study was to understand how the process parameters control the size and properties of submicrometer chitosan particles loaded with DCPA. Solutions of 10 mg/mL chitosan and 2.5 mg/mL DCPA in a 90% acetic acid were electrosprayed under three distinct flow rate conditions: 0.2, 0.5, and 1.0 mL/h. The particles were crosslinked in a glutaraldehyde atmosphere and characterized in terms of their morphology, inorganic content, zeta potential, and minimum inhibitory concentration (MIC) against S. mutans. All conditions showed particles with two similar morphologies: one small-sized with a spherical shape and another larger-sized with a bi-concave shape. All generated a broad particle size distribution, with a similar mean size of ~ 235 nm. The addition of DCPA decreased the zeta potential for all the samples, but it was above 30 mV, indicating a low aggregation potential. The lower flow rate showed the worst efficacy for DCPA incorporation. Antimicrobial activity was greater in chitosan/DCPA particles with flow rate of 0.5 mL/h. It can be concluded that the flow rate of 0.5 mL/h presents the best compromise solution in terms of morphology, zeta potential, MIC, and inorganic content.

Formulation-dependent stability mechanisms affecting dissolution performance of directly compressed griseofulvin tablets

During drug product development, stability studies are used to ensure that the safety and efficacy of a product are not affected during storage. Any change in the dissolution performance of a product must be investigated, as this may indicate a change in the bioavailability. In this study, three different griseofulvin formulations were prepared containing microcrystalline cellulose (MCC) with either mannitol, lactose monohydrate, or dibasic calcium phosphate anhydrous (DCPA). The tensile strength, porosity, contact angle, disintegration time, and dissolution rate were measured after storage under five different accelerated temperature and humidity conditions for 1, 2, and 4 weeks. The dissolution rate was found to decrease after storage for all three batches, with the change in dissolution rate strongly correlating with the storage humidity. The changes in physical properties of each formulation were found to relate to either the premature swelling (MCC/DCPA, MCC/lactose) or dissolution (MCC/mannitol) of particles during storage. These results are also discussed with consideration of the performance- and stability-controlling mechanisms of placebo tablets of the same formulations (Maclean et al., 2021; Maclean et al., 2022).

Exploiting synergistic effects of brittle and plastic excipients in directly compressible formulations of sitagliptin phosphate and sitagliptin hydrochloride

Direct compression (DC) is the simplest and most economical way to produce pharmaceutical tablets. Ideally, it consists of only two steps: dry blending of a drug substance(s) with excipients followed by compressing the powder mixture into tablets. In this study, immediate-release film-coated tablets containing either Sitagliptin phosphate or Sitagliptin hydrochloride were developed using DC technique. After establishing the optimum ratio of ductile and brittle excipients, five formulations were compressed into tablets using a rotary press and finally film coated. Both powders and tablets were examined by standard pharmacopoeial methods. It has been shown that the simultaneous use of excipients with different physical properties, i.e. ductile microcrystalline cellulose and brittle anhydrous dibasic calcium phosphate, produces a synergistic effect, allowing preparation of Sitagliptin DC tablets with good mechanical strength (tensile strength over 2 N/mm2), rapid disintegration (shorter than 2 min), and fast release of the drug substance (85% of the drug is dissolved within 15 min). It was found that the type of calcium phosphate excipient used had a large effect on the properties of the sitagliptin tablets. All formulations developed showed good chemical stability, even when stored under stress conditions (50 °C/80% RH).

Exploring the performance-controlling tablet disintegration mechanisms for direct compression formulations

The design and manufacture of tablets is a challenging process due to the complex interrelationships between raw material properties, the manufacturing settings and the tablet properties. An important factor in formulation and process design is the fact that raw material and tablet properties drive the disintegration and dissolution performance of the final drug product. This study aimed to identify the mechanisms which control tablet disintegration for 16 different immediate-release placebo formulations based on raw material and tablet properties. Each formulation consisted of two fillers (47% each), one disintegrant and a lubricant. Tablets were manufactured by direct compression using four different combinations of the fillers microcrystalline cellulose (MCC), mannitol, lactose and dibasic calcium phosphate anhydrous (DCPA). The disintegration mechanism was primarily driven by the filler combination, where MCC/lactose tablets were identified as wettability controlled, MCC/mannitol tablets as dissolution controlled and DCPA-based tablets (MCC/DCPA and lactose/DCPA) as swelling controlled. A change of 2% in porosity for the wettability controlled tablets (MCC/lactose) caused a significant acceleration of the disintegration process (77% reduction of disintegration time), whereas for swelling controlled tablets (MCC/DCPA) the same porosity change did not considerably impact the disintegration process (3% change in disintegration time). By classifying these formulations, critical formulation and manufacturing properties can be identified to allow tablet performance to be optimised.

Monetite (Dcpa), an Important Calcium Phosphate Compound - its Structure, Processing, and Applications

Monetite (Dibasic calcium phosphate anhydrate, DCPA, CaHPO 4 ) belongs to the sub-category of dibasic calcium phosphates in the diverse calcium phosphate system with its tremendous applications in orthopedics and other biomedical fields. Over the past fifteen years, the research on monetite has increasingly revealed its useful properties. Yet, in comparison to its vastly popular counterparts, hydroxyapatite (HA) and tricalcium phosphates (TCPs), monetite has not gained the attention it deserves. The motivation behind this paper is to provide a comprehensive review of the state-of-the-art of research and development on monetite. After a brief introduction, the paper follows the typical materials science correlations on “Structure-Property-Processing” and relating those aspects to research translation. Indeed, the last few years witnessed increasing numbers of studies on applications of monetite in the form of granules, 3-D printed scaffolds, cements, composites, and coatings with promising outcomes in both in vitro and in vivo studies. The paper concludes with a summary and potential future research directions and its translation. It is hoped that this timely review will present a comprehensive landscape of research on monetite and will enable and entice researchers and engineers across the globe into this important calcium phosphate.

Development of novel dental restorative composites with dibasic calcium phosphate loaded chitosan fillers

The incorporation of antimicrobial agents in restorative dental composites has the potential to slow the development of carious lesions. ObjectiveThe objectives of the present study were to develop experimental composite resins with chitosan or chitosan loaded with dibasic calcium phosphate anhydrous (DCPA) particles and to demonstrate their antimicrobial potential without loss of mechanical properties or biocompatibility. MethodsChitosan and chitosan/DCPA particles were synthetized by the electrospray method. Experimental composites were formulated by adding 0, 0.5, or 1.0 wt% particles into a resin matrix along with 60 wt% barium glass. The degree of conversion and mechanical properties were measured after 1 and 90 days of aging in water after photoactivation. Cytotoxicity and genotoxicity were evaluated using fibroblasts from dental pulp in conditioned medium. The antimicrobial activity against Streptococcus mutans was assessed by crystal violet biofilm assay. ResultsThe experimental restorative composites were not found to be cytotoxic or genotoxic, with cell viability of 93.1 ± 8.0% (p = 0.328) and 3.0 ± 0.8% micronucleus per group (p = 0.1078), respectively. The antimicrobial results showed that all composites with approximately 20% less biofilm (p < 0.001) relative to the control. No chitosan release was detected from the composites, suggesting direct contact of the bacteria with exposed chitosan particles on the surface was responsible for the observed antimicrobial effect. The addition of the chitosan and chitosan/DCPA submicrometer (<250 nm average diameter) particles to restorative composites did not change the degree of conversion, flexural strength, elastic modulus and fracture toughness compared to the control group after 90 days aging in water. SignificanceIt can be concluded that the addition of chitosan or chitosan/DCPA particles in the restorative composites induced antimicrobial activity without compromising the mechanical properties or biocompatibility of the composites.

Physical Barrier Type Abuse-Deterrent Formulations: Mechanistic Understanding of Sintering-Induced Microstructural Changes in Polyethylene Oxide Placebo Tablets.

The main goal of the presented work was to understand changes in the microstructure of tablets, as well as the properties of its main component viz. polyethylene oxide (PEO) as a function of sintering. Key polymer variables and sintering conditions were investigated, and sintering-induced increase in tablet tensile strength was evaluated. For the current study, binary-component placebo tablets comprised of varying ratios of PEO and anhydrous dibasic calcium phosphate (DCP) were prepared at two levels of tablet solid fraction. The prepared tablets were sintered in an oven at 80°C at different time points ranging from 10 to 900min and were evaluated for pore size, tablet expansion (%), and PEO crystallinity. The results showed that for efficient sintering and a significant increase in the tablet tensile strength, a minimum of 50% w/w PEO was required. Moreover, all microstructural changes in tablets were found to occur within 60min of sintering, with no significant changes occurring thereafter. Sintering also resulted in a decrease in PEO crystallinity, causing changes in polymer ductility. These changes in PEO ductility resulted in tablets with higher tensile strength. Formulation variables such as PEO level and PEO particle size distribution were found to be important influencers of the sintering process. Additionally, tablets with high initial solid fraction and sintering duration of 60min were found to be optimal conditions for efficient sintering of PEO-based compacts. Finally, prolonged sintering times were not found to provide any additional benefits in terms of abuse-deterrent properties.

Understanding Compression-Induced Amorphization of Crystalline Posaconazole.

Process-induced phase transformations (PIPTs) of active pharmaceutical ingredients (APIs) can alter APIs' physicochemical properties and impact performance of pharmaceutical drug products. In this study, we investigated compression-induced amorphization of crystalline posaconazole (POSA), where the impact of mechanical stresses and excipients on amorphization were explored. 19F solid-state NMR (ssNMR) was utilized to detect and quantify amorphous content in the compressed tablets, and finite element analysis (FEA) was conducted to understand stress distributions in the compression process. Both applied macroscopic axial stress and shear stress were found to be important to amorphization of crystalline POSA. Punch velocity, an important compression process parameter, had negligible effect on amorphization up to 100 mm/s. Two diluents, microcrystalline cellulose (MCC) and dibasic calcium phosphate anhydrous (DCPA), and one lubricant, magnesium stearate (MgSt), were evaluated for their impact on amorphization in this study. It was found that both MCC and DCPA significantly enhanced amorphization of POSA at a low drug loading (5% w/w). The 1% (w/w) blended lubricant effectively reduced the amorphous content in MCC-POSA tablets; however, it had minimal effect on either neat POSA or DCPA-POSA tablets. Drug loading, or excipient concentration, was demonstrated to have a significant impact on the extent of amorphization. These observed excipient effects support the important role of interparticulate stresses in amorphization of crystalline POSA.

Immediate release tablet formulation of varenicline salicylate and comparative pharmacokinetic study in human volunteers.

PurposeTo develop an immediate release-type tablet containing varenicline salicylate (VRC-S), a smoking cessation agent, formulation and stability studies were performed. The in vitro dissolution and in vivo pharmacokinetic (PK) behavior of the tablets were compared with those of the commercial product (Champix) as a reference.Materials and methodsThe characteristics of the powder were investigated by particle morphology, size distribution, solubility, hygroscopicity, differential scanning calorimetry, and powder X-ray diffraction. Based on the drug–excipient compatibility test, different VRC-S tablets were prepared with the selected excipients through direct compression or wet granulation method and subjected to a dissolution test. The stability of the most promising VRC-S tablet (F4) was evaluated under accelerated conditions (40°C and 75% relative humidity). Further, the dissolution and human pharmacokinetic profiles of the F4 tablet and Champix were compared.ResultsVRC-S showed a positively skewed unimodal size distribution with a specific surface area of 2.02 m2/g, single endothermic peak of 225.2°C in differential scanning calorimetry, crystalline internal structure in powder X-ray diffraction, aqueous solubility of 244.7 mg/mL, and hygroscopicity of 0.256 mg/g. The wet granulation method was preferred for tablet preparation and employed the following excipients: microcrystalline cellulose and anhydrous dibasic calcium phosphate as diluents, croscarmellose sodium as a disintegrant, and colloidal silicon dioxide and magnesium stearate as lubricants. The F4 tablet was stable for 6 months under accelerated conditions. The dissolution of VRC was pH independent, revealing f2 values of 76.49 and 68.38 at pH 1.2 and pH 6.8, respectively. After the oral administration of F4 tablet and Champix to healthy human volunteers, pharmacokinetic parameters, including time to reach the maximum plasma concentration (Tmax), maximum plasma concentration (Cmax), and area under the curve from 0 to infinity (AUCinf), were compared. The values of 90% CI were 0.972–1.035 for Cmax and 0.982–1.075 for AUCinf, which was indicative of the bioequivalence of both products.ConclusionVRC-S–containing F4 tablet might be a good candidate for smoking cessation treatment.

Pharmaceutical excipients properties and screw feeder performance in continuous processing lines: a Quality by Design (QbD) approach

Screw feeder performance is a critical aspect in continuous manufacturing processes. Pharmaceutical excipients, such as mannitol, microcrystalline cellulose, lactose monohydrate, and anhydrous dibasic calcium phosphate can present problems in ensuring a continuous stable feed rate due to their sub-optimal flow properties. In alignment with Quality by Design (QbD) goals, the aim of this work was to identify and explain critical sources of variability of some powder excipients delivery by screw feeding, in particular to continuous processing lines. Pharmaceutical excipients with a wide range of material properties were selected, and the impact of their flow and density properties on screw feeder performance was investigated. The analysis of the powder conveying by the screws was performed at different hopper fills and different screw speeds. A multivariable model involving bulk density (CBD) and parameters from FT4 dynamic downwards testing (SI) and dynamic upwards testing (SE) explained 95.7% of excipients feed rates (p < .001). The study gathers valuable information about the screw feeder performance and input materials properties that can help process understanding and QbD-based development of solid dosage forms in continuous processing lines.

CAUSE-EFFECT RELATIONS AND OPTIMIZATION OF TABLET CONTAINING EUCOMMIA ULMOIDES AND GARDENIA JASMINOIDES SPRAY-DRIED EXTRACTS

Objective: The E. ulmoides and G. jasminoides (EG) tablets containing 67 mg E. ulmoides spray-dried extract (ESE) and 173 mg G. jasminoides spray-dried extract (GSE) were prepared by employing the direct compression method. Due to the poor flowability and compressibility of the two spray-dried extracts, various excipients were added at different ratios so that the blends can be compressed into tablets with the required standards. This study aimed at the cause-effect relations and optimization of the EG tablet formulation.Methods: Different diluents including dibasic calcium phosphate anhydrous (DCPA), silicified microcrystalline cellulose (SMCC), spray-dried lactose (SDL) and the active ingredients (blend of ESE and GSE at the ratio of 67:173, w/w) were separately investigated their own physical properties. The binary mixtures of the active ingredients with different ratios of DCPA, SMCC, and SDL were evaluated their flowability. D-optimal design based on three independent variables (% DCPA, % croscarmellose sodium (CCS) and % SMCC) was applied to evaluate the cause-effect relations and optimize the EG tablet formulation. The weight variation, disintegration time, hardness and friability were investigated as four dependent variables.Results: The flowability of the powders was found to be affected by the particle size distribution, particle shape and density. The three diluents could significantly improve the flowability of the active ingredients. All independent variables had significant effects on the dependent variables. An increase in % SMCC reduced the weight variation, hardness and increased the friability of tablets. Disintegration time was found to be in the negative relations with % CCS. The tablet hardness was in positive relations with % DCPA. The optimized EG tablet formulation composed of 9 % DCPA (w/w), 35 % SMCC (w/w), and 14 % CCS (w/w) of the excipient blend. The weight variation, disintegration time, hardness and friability of the optimized EG tablets were found to be 1.8 %, 11.7 min, 61.4 N, and 0.5 %, respectively.Conclusion: The ESE and GSE could be formulated into tablet by using direct compression method. The cause-effect relations and optimization of EG tablet formulation were studied and reported for the first time.

The relationship among tensile strength, Young's modulus, and indentation hardness of pharmaceutical compacts

Mechanical properties of pharmaceutical materials, e.g., Young's modulus (E), indentation hardness (H), and tensile strength (σt), play an important role in powder compaction process. However, few studies investigated the relationship among these parameters and consequence for tablet compression. Using microcrystalline cellulose, a plastic material, and dibasic calcium phosphate anhydrate, a brittle material, as well as their binary mixtures, we systematically examined the relationship among the three properties. It was found that Young's modulus was proportional to indentation hardness (H/E≈0.036) regardless of the composition and compaction pressure. For a given material, tensile strength was also proportional to E and H but the relationship varied with materials. Higher E and H were required to attain the same σt for a more brittle material.

Roll Compaction/Dry Granulation of Dibasic Calcium Phosphate Anhydrous—Does the Morphology of the Raw Material Influence the Tabletability of Dry Granules?

The influence of raw material particle morphology on the tabletabilty of dry granules was investigated. Therefore, dibasic calcium phosphate anhydrous was used as a model material. One milled grade, 2 agglomerated grades with different porosities, and a functionalized structure, that is, an agglomerate formed by very small primary particles, were included. Particle size, density, and specific surface area of raw materials were measured. The starting materials and 2 fractions of dry granules were compressed to tablets. The tabletability of granules was compared to that of the powders and the influence of specific compaction force, granule size, and lubrication on tablet tensile strength was evaluated. All materials showed a loss in tabletability induced by a previous compaction step but to a varying extent. Only in case of the functionalized calcium phosphate morphology, this effect depended on the specific compaction force. In contrast to the other materials, the tabletability of functionalized calcium phosphate was influenced by the granule size. This effect was not related to an overlubrication as internal and external lubrication resulted in similar tensile strengths. A clear influence of the particle morphology on tablet strength was demonstrated by the study. The functionalized structure showed aspects of a more plastic deformation behavior. The functionalized dibasic calcium phosphate and the more porous agglomerate performed as potential filler/binder in the field of roll compaction/dry granulation.

Experimental determination of residence time distribution in continuous dry granulation

With increasing importance of continuous manufacturing, the interest in integrating dry granulation into a continuous manufacturing line is growing. Residence time distribution measurements are of importance as they provide information about duration of materials within the process. These data enable traceability and are highly beneficial for developing control strategies. A digital image analysis system was used to determine the residence time distribution of two materials with different deformation behavior (brittle, plastic) in the milling unit of dry granulation systems. A colorant was added to the material (20%w/w iron oxide), which did not affect the material properties excessively, so the milling process could be mimicked well. Experimental designs were conducted to figure out which parameters effect the mean residence time strongly. Moreover, two types of dry granulation systems were contrasted. Longer mean residence times were obtained for the oscillating mill (OM) compared to the conical mill (CM). For co-processed microcrystalline cellulose residence times of 19.8–44.4s (OM) and 11.6–29.1s (CM) were measured, mainly influenced by the specific compaction force, the mill speed and roll speed. For dibasic calcium phosphate anhydrate residence times from 17.7–46.4 (OM) and 5.4–10.2s (CM) were measured, while here the specific compaction force, the mill speed and their interactions with the roll speed had an influence on the mean residence time.

Lubrication with magnesium stearate increases tablet brittleness

Tablet brittleness index (TBI) quantifies tablet fracture behavior, which strongly correlates with tablet porosity and tensile strength. The goal of this work was to quantify the influence of lubrication on tablet brittleness. Magnesium stearate was used as a lubricant. Several common tablet excipients, i.e., starch, lactose, microcrystalline cellulose (MCC), and dibasic calcium phosphate anhydrate (DCPA), and a binary mixture between lactose and MCC were studied. Tablet tensile strength (σ) and TBI at zero porosity (σ0 and TBI0) were obtained from nonlinear regression of data of all powders to evaluate the relationship between brittleness and bonding strength of pore-free tablets. The results show that lubrication by magnesium stearate led to decrease in σ0 and increase in TBI0. The effect was more profound for both a longer blending time and a higher amount of magnesium stearate. In addition, the TBI of the binary mixture was successfully predicted from the fitted parameters of lactose and MCC using the power mixing rule. Such effects of lubrication on tablet brittleness should be considered during formulation development to avoid unexpected quality issues.

Design and development of polyethylene oxide based matrix tablets for verapamil hydrochloride.

In the present investigation an attempt has been made to increase therapeutic efficacy, reduced frequency of administration and improved patient compliance by developing controlled release matrix tablets of verapamil hydrochloride. Verapamil hydrochloride was formulated as oral controlled release matrix tablets by using the polyethylene oxides (Polyox WSR 303). The aim of this study was to investigate the influence of polymer level and type of fillers namely lactose (soluble filler), swellable filler (starch 1500), microcrystalline cellulose and dibasic calcium phosphate (insoluble fillers) on the release rate and mechanism of release for verapamil hydrochloride from matrix tablets prepared by direct compression process. Higher polymeric content in the matrix decreased the release rate of drug. On the other hand, replacement of lactose with anhydrous dibasic calcium phosphate and microcrystalline cellulose has significantly retarded the release rate of verapamil hydrochloride. Biopharmaceutical evaluation of satisfactory formulations were also carried out on New Zealand rabbits and parameters such as maximum plasma concentration, time to reach peak plasma concentration, area under the plasma concentration time curve(0-t) and area under first moment curve(0-t) were determined. In vivo pharmacokinetic study proves that the verapamil hydrochloride from matrix tablets showed prolonged release and were be able to sustain the therapeutic effect up to 24 h.

Surface micropatterning with calcium phosphate ceramics by micromoulding in capillaries

Event Abstract Back to Event Surface micropatterning with calcium phosphate ceramics by micromoulding in capillaries David Barata1, 2, Daniel De Melo Pereira1, 2, Alessandro Resmini3, Sjöerd A. Veldhuis3, Clemens A. Van Blitterswijk1, 2, J E. Ten Elshof3 and Pamela Habibovic1, 2 1 MIRA Institute for Miomedical Technology and Technical Medicine, University of Twente, Department of Tissue Regeneration, Netherlands 2 MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Instructive Biomaterials Engineering, Netherlands 3 MESA+ Institute for Nanotechnology, University of Twente, Inorganic Materials Science, Netherlands Introduction: Current design of biomaterials for regenerative medicine is progressing towards greater control over the biological response in vivo, along with the evolution of the concept of biocompatibility from bioinert to bioactive[1]. Surface patterning is a promising method to achieve spatial control over cell behaviour by physico-chemical cues such as surface chemistry or topography[2]. While a variety of techniques exist to develop patterns of polymers or biomolecules, patterning ceramic materials is explored to a lesser extent and requires further research[3]. This is particularly interesting for the field of bone regeneration, where calcium phosphate (CaP) ceramics are widely used for their close resemblance to bone mineral and associated bioactivity in terms of osteoconduction and osteoinduction[4]. Here we present an approach to micropatterning of surfaces with CaPs by employing micromoulding in capillaries (MIMIC), a method previously shown suitable for patterning zirconia[5]. Materials and Methods: MIMIC was employed to create patterns of dibasic calcium phosphate anhydrous (DCPA) on a flat silicon substrate. Briefly, a polydimethylsiloxane (PDMS) mould with grooves was placed on the silicon substrate to create channels. After air plasma, CaP solution was infiltrated and controlled heating facilitated nucleation and crystal growth inside the microchannels. After completion, the PDMS mould was removed. Selected samples were further annealed to convert DCPA into β-tricalcium phosphate (β-TCP). Substrates were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). Biocompatibility was assessed by culturing MG-63 osteoblast-like cells on the Si-CaP substrates and analysing cell morphology, metabolic activity and proliferation over a period of 7 days. Results and Discussion: CaP bioceramic patterns were successfully formed by nucleation and growth of crystals in the microchannels. The SEM (Figure 1) and the EDS analyses revealed patterns that were confined to the channels used for patterning. The patterns consisted of flower-like crystals varying in size between 5 and 25 μm. XRD pattern showed peaks characteristic of DCPA (before annealing) and of β-TCP (after annealing). The analysis of cell morphology on the patterns showed the effect of the patterns on cell orientation, an effect that was dependent on the pattern size. Metabolic activity of MG-63 cells showed an increasing trend during the 7-day culture, as did the total DNA amount, confirming the biocompatibility of these materials. The results demonstrated that MIMIC is a suitable technique to fabricate micropatterns of CaP against a chemically different background, and that the created micropatterns can be used to spatially control cell behaviour. Conclusion: MIMIC is a promising technique for patterning of CaP ceramics. Further improvements on the patterning method will focus on obtaining different CaP phases, improving control over the morphology and homogeneity of the CaP pattern, and increasing the complexity of the patterns. DB gratefully acknowledges the financial support of the NIRM (Netherlands Institute of Regenerative Medicine); This research has been in part made possible with the support of the Dutch Province of Limburg