Application of the combination of ball-milling and hot-melt extrusion in the development of an amorphous solid dispersion of a poorly water-soluble drug with high melting point

The aim of the study was to develop an amorphous solid dispersion of a poorly water-soluble drug with high melting point by ball milling and hot melt extrusion as a co-processing method. Solid dispersion systems were prepared by ball milling-hot melt extrusion and then compared with those prepared with hot melt extrusion. The effects of three process parameters in the co-processing method, namely, barrel temperature, screw speed, and cooling rate, were systematically studied. The physical state of prepared solid dispersion was characterized by differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, phase solubility, and dissolution study. The Resveratrol–Eudragit® EPO system exhibited good miscibility and significant dissolution enhancement. Resveratrol in the amorphous solid dispersion existed in an amorphous state and had molecular interactions with Eudragit® EPO. Stability studies showed no apparent difference in the physical state of the solid dispersion after 6 months. In conclusion, combining ball milling with hot melt extrusion is a promising method for preparing the amorphous solid dispersion of a poorly water-soluble drug with high melting point.

The aim of the study was to develop an amorphous solid dispersion of a poorly water-soluble drug with high melting point by ball milling and hot melt extrusion as a co-processing method.     

The effect of egg albumin on the crystalline properties of carbamazepine in sustained release hydrophilic matrix tablets and in aqueous solutions.

The influence of egg albumin (EA) on the crystal habit properties of carbamazepine (CBZ) in aqueous solutions, solid-state, and in sustained release matrix tablets was investigated using differential scanning calorimetry (DSC), hot-stage microscopy (HSM), X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and contact angle goniometer (CAG). The results suggest that in solid-state mixtures, EA affected the polymorphic transitions of CBZ from the beta to the alpha form. In hydrated matrix tablets and aqueous solutions, EA influenced the conversion rate of CBZ to the dihydrate form depending on EA concentration. It was found that increasing EA concentration enhanced CBZ dihydrate aggregation, an effect that leads to the formation of crystals with high mechanical strength and decrease of CBZ solubility. Possible mechanisms, which explain crystal growth and aggregation, as well as alteration of CBZ polymorphic transitions in the solid-state, gel layer, and in aqueous solution were suggested. In the gel layer of hydrated tablets the kinetics of CBZ transformation to the dihydrate form, crystal growth and aggregation were influenced by various processes: matrix hydration, erosion mechanism and the formation of metastable conditions, which favor aggregation and growth. The release kinetics of CBZ from the matrix highly correlated with the crystalline and morphological changes occurring in the matrix.     

Isostructural cocrystals of metaxalone with improved dissolution characteristics

Muscle relaxant and pain reliever metaxalone (MET) is a biopharmaceutical classification systems (BCS) class II drug with poor aqueous solubility and high permeability. The presence of an aromatic skeleton and cyclic carboxamate moiety are the probable reasons for the decreased aqueous solubility, which impacts on its low bioavailability. A high dose (800 mg) of the drug often creates adverse side effects on the central nervous system that needs urgent remedy. Cocrystallization of MET with nicotinamide (NAM), salicylamide (SAM), and 4-hydroxybenzoic acid (HBA) resulted in multicomponent solids that were characterized by PXRD, DSC and single crystal X-ray diffraction. Cocrystals with SAM and NAM form 2D isostructural cocrystals, whereas with HBA the result is a differently packed cocrystal hydrate (or anisole hemisolvate) depending upon the crystallization medium. Similar to the reported MET cocrystals, these cocrystals also confirm the preference for an imide⋯imide homosynthon in the drug. The dominance of the drug–drug homodimer over drug-coformer heterodimers was demonstrated based on binding energy calculations. Further, powder dissolution experiments in pH 6.8 phosphate buffer indicate that the cocrystals improved the apparent solubility compared to the native drug by 3–9 fold. The absence of stronger heterosynthons between MET and the coformers, their lower melting points and the high solubility of the coformers are the probable reasons for the enhanced solubility of the bioactive component. The MET–NAM cocrystal exhibited the highest solubility/dissolution rate among the three binary solid forms, which may offer improved bioavailability and a lower dose with minimal side effects.

Metaxalone forms isostructural cocrystals with nicotinamide and salicylamide that offer a solubility advantage compared to the native drug. A drug–drug homosynthon is retained in all the cocrystal structures.     

Co-amorphous palbociclib–organic acid systems with increased dissolution rate,enhanced physical stability and equivalent biosafety

The preparation of co-amorphous drug systems by adding a small molecular excipient is a promising formulation in the modern pharmaceutical industry to improve the solubility, dissolution rate, and bioavailability of poorly soluble drugs. In this study, palbociclib co-amorphous systems with organic acids (succinic, tartaric, citric, and malic acid) at molar ratios of 1 : 1 were prepared by co-milling and characterized by differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR) and solid-state nuclear magnetic resonance (SS-NMR). These solid-state investigations have confirmed the formation of co-amorphous salts between PAL and organic acids. The solubility, dissolution rate and stability of the four co-amorphous drug systems were significantly improved compared with these of crystalline and amorphous palbociclib. The biosafety of the co-amorphous drug systems was the same as that of palbociclib without affecting the efficacy of the drug and eliciting toxic side effects. These comprehensive approaches for the palbociclib–acid co-amorphous drug systems provided a theoretical basis for its clinical applications.

The study of co-amorphous systems presented a safe and effective formulation technology for the development of new palbociclib solid forms with great dissolution rates, good physical stability, and high bioavailability.     

Design and formulation of polymeric nanosponge tablets with enhanced solubility for combination therapy

Three drugs namely caffeine, paracetamol, and aceclofenac are commonly used for treating various acute and chronic pain related ailments. These 3 drugs have varied solubility profiles, and formulating them into a single tablet did not have the desired dissolution profile for drug absorption. The objective of the present research was to tailor the drug release profile by altering drug solubility. This was achieved by loading the drug into nanosponges. Here, three-dimensional colloidal nanosponges were prepared using β-cyclodextrin with dimethyl carbonate as a cross-linker using the hot-melt compression method. The prepared nanosponges were characterized by FTIR, ¹H NMR spectroscopy, DSC, XRPD studies and SEM. The FTIR and DSC results obtained indicated polymer-drug compatibility. The ¹H NMR spectroscopy results obtained indicated the drug entrapment within nanosponges with the formation of the inclusion complex. XRPD studies showed that the loaded drug had changed crystalline properties altering drug solubility. SEM photographs revealed the porous and spongy texture on the surface of the nanosponge. Box–Behnken experimental design was adopted for the optimization of nanosponge synthesis. Among the synthesized nanosponges containing paracetamol, aceclofenac and caffeine, batch F3–P31, F3–A31 and F3–C31 were considered optimized. Their particle size was 185, 181 and 199 nm with an entrapment efficiency of 81.53, 84.96, and 89.28% respectively. These optimized nanosponges were directly compressed into tablets and were studied for both pre and post-compression properties including in vitro drug release. The prepared tablet showed desired drug dissolution properties compared to the pure drug. The above outcomes indicated the applicability of nanosponges in modulating the drug release with varied solubility for combination therapy.

Polymeric nanosponges as potential carriers for successful combination therapy of poorly soluble drugs (paracetamol, aceclofenac, caffeine).     

Design of controlled-release solid dosage forms of alginate and chitosan using microwave.

The influence of microwave irradiation on the drug release properties of alginate, alginate-chitosan and chitosan beads was investigated. The beads were prepared with the highest possible concentration of polymer by an extrusion method. Sulphathiazole was selected as a model drug. The beads were subjected to microwave irradiation at various combinations of irradiation power and time. The profiles of drug dissolution, drug content, drug stability, drug polymorphism, drug-polymer interaction, polymer crosslinkage and complexation were determined by dissolution testing, drug content assay, differential scanning calorimetry (DSC) and fourier transform infra-red spectroscopy (FTIR). The chemical stability of the drug entrapped in the beads was unaffected by the microwave irradiation. However, the drug in the chitosan beads underwent polymorphic changes. Polymorphic changes were prevented by means of drug-alginate interaction in alginate and alginate-chitosan beads. Changes in the polymorphic state of drug were found to have insignificant effect on the drug release profiles of chitosan beads. The release-retarding property of alginate and alginate-chitosan beads was significantly enhanced by subjecting the beads to microwave irradiation. Positively charged calcium ions and chitosan are known to interact with negatively charged alginate. DSC and FTIR analyses indicated that the reduction in rate and extent of drug released from the treated beads was primarily due to additional formation of non-ionic bonds, involving alginate crosslinkage and alginate-chitosan complexation. The results showed that microwave technology can be employed in the design of solid dosage forms for controlled-release application without the use of noxious chemical agents.     

A new agglomerated KSR-592 beta-form crystal system for dry powder inhalation formulation to improve inhalation performance in vitro and in vivo.

A new agglomerated KSR-592 (steroid) beta-form needle-like crystals with lactose system for dry powder inhalation (DPI) was developed to improve inhalation performance with Jethaler. The drug agglomerates were prepared by the method of spherical agglomeration in liquid so as to control the particle size and the mechanical strength of agglomerates by changing the agitation speed of the agglomeration system. The agglomerates mixed with lactose particles for the DPI formulation were effectively disintegrated into respirable fine particle in the milling chamber of the device (Jethaler) when inhaled. The DPI formulation with these agglomerates exhibited ideal fluidity and provided a larger fine particle fraction (FPF: 29.7%) than the formulation with agglomerates consisting of alpha-form (plate-like) crystals (24.5%). The air-flow rate of inhalation had no effect on the disintegration properties of these agglomerates, suggesting a reliable inhalation performance in vivo. Further, an in vivo test of the aerosolized KSR-592 (beta-form) crystals having the same particle size distribution as those in the aerosol produced by Jethaler was conducted by means of a dry powder inhalation testing system using Brown Norway rats. Inhaled KSR-592 (beta-form) crystals were found to be uniformly deposited in the lungs of Brown Norway rat sensitized by ovalbumin (OA) and suppressed the increase in eosinophil number in the lungs after OA challenge.     

Influences of novel microwave drying on dissolution of new formulated naproxen sodium

Drying of a pharmaceutical composition is an important step during its processing, which can affect its quality attributes including its texture, dispersion of the drug within the formulation, drug dissolution kinetics and eventually the drug''s efficacy. This study presents the influence of varying drying techniques on the textural properties of the wet granulated formulation consisting of the drug naproxen sodium (NapSod) during the drying process. A new pharmaceutical formulation consisting of the NapSod drug was prepared by wet granulation and dried by novel microwave drying (MW), freeze drying (FD), vacuum drying (VD), and convective drying (CD) techniques before being processed in the form of tablets. The dissolution rate of NapSod from the tablet was measured in gastric (pH = 1.3) and intestinal fluid (pH = 6.8) mediums. The drug release was found to be influenced by the specific surface area, size distribution and the crystalline structure of dried particles, which were found to vary with the type of drying technique used as confirmed by the results of XRD, FTIR, SEM and particle size analyses. This study shows that using microwave technique to dry pharmaceutical granules containing a polar drug, such as NapSod, is an efficient and economical process, which can maintain the drug release at an appropriate rate to realize its desired pharmaceutical effect.

Novel microwave mediated drying of naproxen sodium has been shown as an efficient drying technique as well as exhibiting a critical role in improving the dissolution kinetics.     

A novel drug–drug coamorphous system without molecular interactions: improve the physicochemical properties of tadalafil and repaglinide

Tadalafil and repaglinide, categorized as BCS class II drugs, have low oral bioavailabilities due to their poorly aqueous solubilities and dissolutions. The aim of this study was to enhance the dissolution of tadalafil and repaglinide by co-amorphization technology and evaluate the storage and compression stability of such coamorphous system. Based on Flory–Huggins interaction parameter (χ ≤ 0) and Hansen solubility parameter (δ_t ≤ 7 MPa^0.5) calculations, tadalafil and repaglinide was predicted to be well miscible with each other. Coamorphous tadalafil–repaglinide (molar ratio, 1 : 1) was prepared by solvent-evaporation method and characterized with respect to its thermal properties, possible molecular interactions. A single T_g (73.1 °C) observed in DSC and disappearance of crystallinity in PXRD indicated the formation of coamorphous system. Principal component analysis of FTIR in combination with Raman spectroscopy and Ss ¹³C NMR suggested the absence of intermolecular interactions in coamorphous tadalafil–repaglinide. In comparison to pure crystalline forms and their physical mixtures, both drugs in coamorphous system exhibited significant increases in intrinsic dissolution rate (1.5–3-fold) and could maintain supersaturated level for at least 4 hours in non-sink dissolution. In addition, the coamorphous tadalafil–repaglinide showed improved stability compared to the pure amorphous forms under long-term stability and accelerated storage conditions as well as under high compressing pressure. In conclusion, this study showed that co-amorphization technique is a promising approach for improving the dissolution rate of poorly water-soluble drugs and for stabilizing amorphous drugs.

The coamorphous tadalafil–repaglinide (molar ratio, 1 : 1) prepared by solvent-evaporation method significantly improve the physicochemical properties of tadalafil and repaglinide.     

Setting bioequivalence requirements for drug development based on preclinical data: optimizing oral drug delivery systems.

The recently proposed Biopharmaceutics Classification System can be used to classify drugs and set standards for scale-up and post-approval changes as well as standards for in vitro/in vivo correlation for immediate and controlled release products. This classification scheme is based on determining the underlying process that is controlling the drug absorption rate and extent, namely, drug solubility and intestinal membrane permeability. Theoretical analysis and experimental results suggest that a permeability/solubility classification scheme can be used to set more rationale drug standards. In particular, high solubility/high permeability, rapidly dissolving drugs may be regulated on the basis of a single point rapid dissolution test while low solubility dissolution rate limited drugs can be regulated based on an in vitro dissolution test that reflects the in vivo dissolution process. This dissolution test may include multiple time points, media change, as well as surfactants in order to reflect the in vivo dissolution process and would be used by the manufacturer for requesting a waiver from a bioequivalence (BE) trial. For controlled release products, the regulation of bioequivalence standards is more complex due to the potential differences in position-dependent permeability/solubility and metabolism of drugs along the gastrointestinal tract. These differences may result in drug absorption rates that are highly transit time dependent. This paper will present the current status of the biopharmaceutic drug classification scheme, the underlying developed data base and its application to optimizing IR and CR products.     

Preparation and evaluation of a melt pelletised paracetamol/stearic acid sustained release delivery system.

The potential of a sustained release formulation for paracetamol produced by melt pelletisation was investigated. The chosen formulation was based on the combination of stearic acid as a melting binder and anhydrous lactose as a filler. After determination of the size distribution, the pellet characterisation included scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), specific surface area and true density determination. Hence, the in vitro release from every single size fraction (2000, 1250, 800, 630, <630 microm) was evaluated and the release mechanism was analysed with the help of an appropriate mathematical model. The results of drug content and superficial atomic composition were found to be constant in all pellets size fractions, attesting the ability of melt pelletisation in a high shear mixer to form a product with homogeneous composition. The mathematical model is built on the hypotheses that drug diffusion and solid drug dissolution in the release environment are the key phenomena affecting drug release kinetics. Smaller classes apart (particles are not perfectly spherical), the comparison between model best fitting and experimental data indicated the reasonability of these hypotheses. Moreover, model reliability is proved by its ability of predicting drug release from a known mixture of the above mentioned particles classes.     

Cyclodextrin and its derivatives as effective excipients for amorphous ulipristal acetate systems

Many efforts have been devoted to screening new solid-state forms of poorly soluble drugs in the pharmaceutical industry, thus modulating the drug properties without changing the pharmacological nature. It is a wise strategy to prepare amorphous series with cyclodextrin (CD) and its derivatives as excipients to enhance the aqueous solubility, dissolution, and bioavailability of water-insoluble drugs. In this study, four binary amorphous mixtures of ulipristal acetate (UPA) with CDs (β-CD, γ-CD, dimethyl-β-CD, hydroxypropyl-β-CD) were prepared by the co-milling method and characterized in the solid-state. According to powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC), UPA existed in the noncrystalline form in the four binary amorphous mixtures. Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) indicated that UPA interacted with the four CDs, which was also verified by molecular docking. Compared with the crystalline and amorphous UPA, the solubility, dissolution, and stability of the drug in the four amorphous UPA systems were significantly improved, so they were considered potentially advantageous solid forms. Our research shows that CDs can be used as new effective excipients in amorphous systems for active pharmaceutical ingredients (API).

Probing into the amorphous mixtures of ulipristal acetate and cyclodextrins.     

Development and evaluation of bio-dissolution systems capable of detecting the food effect on a polysaccharide-based matrix system.

Methods are proposed and tested for mimicking the in vitro food effect on controlled release dosage forms, using USP dissolution apparatus 3. Using in vivo data a pH and time profile was constructed, and the methods utilized either presoaking in peanut oil or continuous oil contact to mimic the presence of a high fat meal. A water soluble drug (propranolol hydrochloride, class 1 by BCS) was used as a model material. Both methods were able to confirm that a labile multiparticulate system (Inderal LA) was susceptible to such in vitro effects. A hydrocolloid matrix tablet showed low susceptibility to either technique. There was a good correlation between methods, which may indicate that the oil presoaking method, which is less time consuming to carry out and leads to more simple subsequent analysis, may be sufficient to identify dosage forms susceptible to physical food effects.     

Starch acetate as a tablet matrix for sustained drug release.

The aim of this study was to investigate the effect of a high degree on substitution (DS) on starch acetate (SA) and SA concentration on tablet properties. SAs with a DS of 2.6 and 3.0 were used as matrix formers with propranolol hydrochloride (PH) as a model drug. The SA-3.0 powder had better compactibility than the SA-2.6 powder. A decrease in SA concentration decreased compactibility of PH/SA blended powders when compared to neat SA powders. In general, drug release was considerably slower from SA-3.0 matrices than from SA-2.6 matrices. Also, a decrease in SA concentration increased the drug release rate. Water penetration into 80% (w/w) SA-3.0 matrices was incomplete during 24-h dissolution tests. Diffusion path length increased with time and PH was released by Fickian diffusion. However, all other PH/SA tablets were completely hydrated during dissolution tests. Macroscopic cracks were formed during dissolution, which increased area available for Fickian diffusion and resulted in slow attenuation of the drug release rate. Crack formation, not been reported earlier, must be taken into account in order to understand drug release from SA matrices.     

Preliminary spherical agglomerates of water soluble drug using natural polymer and cross-linking technique

The objective of this study was to use the polymer, carrageenan (Gelcarin, GP 812) in an attempt to control the drug release from spheres prepared by cross-linking technique. The variables studied were the drug levels; polymer levels and the cross-linking agent. The aqueous dispersion of the drug and polymer was dropped by a disposable syringe into 3% w/v aqueous solution of cross-linking agent, and the droplets instantaneously formed spheres. Spherical agglomerates containing 77.6% w/w drug could be prepared and the physical properties of the spheres was dependent on the drug and polymer levels and also on the cross -inking material used. The drug release from spheres containing 11.9% w/w drug prepared by using 3% w/v cross-linking agent was higher than those containing 77.6% w/w drug. Carrageenan polymer can exert control over the rate and amount of drug released from spheres prepared by cross-linking technique.     

Translocation of drug particles in HPMC matrix gel layer: effect of drug solubility and influence on release rate

The aim of this work was to study the release mechanisms of drugs having different solubility (buflomedil pyridoxalphosphate 65%, sodium diclofenac 3.1%, nitrofutantoin 0.02% w/v,) from hydroxypropyl methylcellulose (HPMC) matrices by concomitantly studying swelling, diffusion and erosion fronts movement and drug delivery. The main goal was to clarify the role played by polymer swelling in drug transport. The results showed that the rate and amount of drug released from swellable matrices was dependent not only from drug dissolution and diffusion but also from solid drug translocation in the gel due to polymer swelling. In fact, as drug solubility decreased, the slower drug dissolution rate in the gel layer allowed drug particles to be transported close to the matrix erosion front. The presence of solid particles in the gel reduced the swelling and the entanglement of polymer chains and affected the resistance of gel towards erosion. As a consequence, the matrix became more erodible. The erosive delivery accelerated after the matrix had been completely transformed into the rubbery state, particularly when a considerable amount of solid drug particles remained in the gel phase.     

Design, optimization and evaluation of domperidone coevaporates.

Coevaporates of domperidone were prepared using different polymers by solvent evaporation technique. Ethyl cellulose and hydroxypropyl methylcellulose phthalate were used in preparation of coevaporates. The coevaporates were characterized by X-ray diffraction studies, IR spectrophotometry and differential scanning calorimetry. The dissolution behavior of coevaporates was studied using buffer solution of pH 1.2 for the first 2 h and that of pH 6.8 thereafter up to 12 h. A two-factor, three-level design was used to quantitate the effect of polymers on dissolution profile of domperidone. The drug release rate was found to be dependent on the concentration of polymers in the coevaporates. Dissolution of drug in a pH 6.8 buffer improved with increasing concentration of hydroxypropyl methylcellulose phthalate in coevaporates. Bioavailability studies in human volunteers confirmed that domperidone coevaporates sustained drug release.     

Mixed surfactant based (SNEDDS) self-nanoemulsifying drug delivery system presenting efavirenz for enhancement of oral bioavailability

This study aims to develop a self-nanoemulsifying drug delivery system (SNEDDS) based on non-ionic surfactant mixtures to improve the oral bioavailability of efavirenz (EFZ) categorized as a class II according to the BCS, for HIV- therapy. The result of solubility studies of EFZ in various excipients utilized for construction of the pseudo ternary phase diagram containing surfactant mixtures. Surfactants in 1:1 combination are used with different co-surfactants in different ratio to delineate the area of monophasic region of the pseudo ternary phase diagram. Different accelerated physical stability studies and self-emulsification assessment were performed on the formulations. The formulations clearing the above studies are considered for percentage transmittance and turbidity analysis. The globule size distributions of post diluted SNEDDS having percentage transmittance above 90 were estimated. The TEM analysis of two optimized post diluted SNEDDS formulations further confirm the size in nanometric range (below 50 nm). FT-IR studies showed the retention of the characteristic peaks of EFZ in the preconcentrate. The in vitro dissolution profile of SNEDDS established advantages of SNEDDS over plain drug as more than 80% drug was released within 30 min in case of optimized SNEDDS while it was approximately 18.3% in the case of plain drug powder. Pharmacokinetic parameters were calculated after performing the in vivo studies of best optimized formulation in rats. The Pharmacokinetic data reveal a 2.63 fold increase in AUC_(0-∞) in comparison to plain EFZ suspension. The designed delivery system showed the faith in generating an effective formulation of EFZ for HIV treatment.     

New experimental melting properties as access for predicting amino-acid solubility

The properties of melting are required for the prediction of solubility of solid compounds. Unfortunately, direct determination of the enthalpy of fusion and melting temperature by using conventional DSC or adiabatic calorimetry is often not possible for biological compounds due to decomposition during the measurement. To overcome this, fast scanning calorimetry (FSC) with scanning rates up to 2 × 10⁴ K s⁻¹ was used in this work to measure the melting parameters for l-alanine and glycine. The enthalpy of fusion and melting temperature (extrapolated to zero heating rate) were Δ_fusH = (22 ± 5) kJ mol⁻¹ and T_fus = (608 ± 9) K for l-alanine, and Δ_fusH = (21 ± 4) kJ mol⁻¹ and T_fus = (569 ± 7) K for glycine. These melting properties were used in the modeling framework PC-SAFT to predict amino-acid solubility in water. The pure-component PC-SAFT parameters and one binary parameter were taken from literature, in which these parameters were fitted to solubility-independent thermodynamic properties such as osmotic coefficients or mixture densities. It was shown that this allowed accurately predicting amino-acid solubility in water over a broad temperature range. The combined methodology of PC-SAFT and FSC proposed in this work opens the door for predicting solubility of molecules that decompose before melting.

New experimental melting properties combined with PC-SAFT allow quantitative solubility predictions of amino acids in water.     

模拟体液浸泡法评价柠檬酸钙的生物学特性

背景：柠檬酸钙本身的溶解性能优于磷酸钙、硫酸钙等其他钙生物材料,并且合成的柠檬酸钙致密性良好,在降解过程中可高效平稳释放钙离子,所以更适合用于骨折缺损的填充,为骨折愈合初期提供所需要的钙离子。 目的：将天然生物矿化牡蛎壳和柠檬酸反应生成生物型柠檬酸钙生物材料,以期望在骨折愈合修复方面得到良好的应用。 方法：通过球磨机粉碎天然生物矿化的牡蛎壳,再经研磨制备成适合粒径的牡蛎壳粉,与柠檬酸反应得到生物型柠檬酸钙,再经研磨,过筛,得到适宜大小的柠檬酸钙颗粒。应用X射线和FT-IR光谱研究材料的结构和组分,扫描电子显微镜观察材料的表面形态,模拟体液实验评价其生物特性。 结果与结论：牡蛎壳粉末与饱和柠檬酸发生化学反应,转化生成了柠檬酸钙材料,并且晶体结构排列有序,形态紧密,晶体之间结合紧凑,具有一定的力学性能,这种结构也有利于延长材料的降解时间,平稳释放钙离子。柠檬酸钙在降解吸收过程中并未明显改变体液的pH值,整个pH值波动于7.20-7.46之间,对人体细胞的刺激性小。随着柠檬酸钙材料的逐渐降解,溶液中Ca2＋浓度逐渐增大,且释放相对平缓,最终达到适宜成骨细胞增殖分化所需的胞外钙浓度,逐步稳定在7 mmol/L左右。表明以天然牡蛎壳为原料制备的柠檬酸钙具有优良的生物特性,作为人工骨材料具有天然的优越性。