Copolymerization and polymer blending of trimethylene carbonate and adipic anhydride for tailored drug delivery

The copolymerization in bulk and solution of trimethylene carbonate (TMC) with adipic anhydride (AA) as well as the blending of homopolymers are described. We show experimentally that the components are not copolymerizable but partially miscible, forming a microscopic dispersion without any visible signs of phase separation. Poly(adipic anhydride) (PAA) functions as a plasticizer, permitting an increase in the erosion rate by increasing the porosity and hydration. Drug delivery from the blends was evaluated. A statistical factorial model was designed to explore the influence of three important blend parameters and their interactions, making it possible to predict the erosion and drug‐release behavior of the blend matrices. The PAA:poly(trimethylene carbonate) (PTMC) ratio and molecular weight of the polycarbonate component significantly influence the drug‐release performance, mass loss, and degree of plasticization. The interaction among these factors also influences the blend properties. Plasticization of PTMC enhances the drug release to an extent that is dependent on the amount of PAA used. We demonstrate that blending offers a convenient alternative to copolymerization for the preparation of polymer matrices with predictable drug delivery. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 72: 227–239, 1999     

Influence of molecular structure on the degradation mechanism of degradable polymers: In vitro degradation of poly(trimethylene carbonate), poly(trimethylene carbonate-co-caprolactone), and poly(adipic anhydride)

Relationships between molecular structure and the degradation mechanism of degradable polymers are of special interest for temporary medical applications. The in vitro degradation study of three aliphatic polymers—poly(trimethylene carbonate) (PTMC), poly(trimethylene carbonate-co-caprolactone) (PTMC-PCL), and poly(adipic anhydride) (PAA)—revealed that these polymers exhibit degradation times from several years (PTMC) to 1 day (PAA). PTMC degraded unexpectedly slow, accompanied by very small changes in weight loss, molecular weight (SEC), and in morphology (DSC, SEM). The degradation was independent of initial molecular weight, ionic strength of the water solution, temperature, and shaking motions. The copolymer PTMC-PCL showed a higher degradation rate compared to PTMC, with preferential degradation of amorphous parts leading to an increase in % crystallinity. The surprisingly rapid degradation of PAA showed characteristics typical for a surface-like eroding system in contrast to PTMC and PTMC-PCL. The degradation products corresponded to the repeating unit of the polymers. The hydrolysis rate increases in the order carbonate, ester, anhydride, and by combining different molecular structures we achieve specific degradation behavior. A change in hydrolysis rate of the labile bond is predicted by altering the electronegativity of groups near the carbonyl-oxygen region. © 1995 John Wiley & Sons, Inc.     

Synthesis and characterization of biodegradable low molecular weight aliphatic polyesters and their use in protein‐delivery systems

Poly(lactic acid) (PLA) and poly(lactic‐co‐GA) (PLGA) with low molecular weights were synthesized by a one‐step polycondensation of lactic acid (LA) with glycolic acid (GA) molecules using stannous octoate as a catalyst at 160°C. A high yield (>80%) of all the polymers was obtained in the study. The PLA and PLGA copolymers were characterized by ¹H‐NMR, GPC, and DSC measurements, etc. We elaborated HSA‐loaded microspheres based on PLA and PLGA copolymers with different monomer ratios (LA/GA = 85:15, 75:25, 65:35, and 50:50) by the solvent‐extraction method based on the formation of double w/o/w emulsion. Microspheres were characterized in terms of the morphology, size, and encapsulation efficiency (E.E.). The highest E.E. (69.3%) of HSA was obtained for HSA‐loaded PLGA (65/35) microspheres among all the formulations. In vitro matrix degradation and protein release of these microspheres were performed in phosphate‐buffer saline (PBS; 154 mM, pH 7.4). The degradation profiles were characterized by measuring the loss of the microsphere mass and the decrease of the polymer intrinsic viscosity. The release profiles were investigated from the measurement of the protein presented in the release medium at various intervals. It was shown that the matrix degradation and protein‐release profiles were highly LA/GA ratio‐dependent. It is suggested that these matrix polymers may be optimized as carriers in protein‐ and peptide‐delivery systems for different purposes. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 1848–1856, 2004     

Preparation of core–shell poly(acrylic acid)/polystyrene/SiO2 hybrid microspheres

Core–shell poly(acrylic acid)/polystyrene/SiO₂ (PAA/PS/SiO₂) hybrid microspheres were prepared by dispersion polymerization with three stages in ethanol and ethyl acetate mixture medium. Using vinyltriethoxysilane (VTEOS) as silane agent, functional silica particles structured vinyl groups on surfaces were prepared by hydrolysis and polycondensation of tetraethoxysilane and VTEOS in core stage. Then, the silica particles were used as seeds to copolymerize with styrene and acrylic acid sequentially in shell stage I and stage II to form PAA/PS/SiO₂ hybrid microspheres. Transmission electron microscope results show that most PAA/PS/SiO₂ hybrid microspheres are about 40 nm in diameter, and the silica cores are about 15 nm in diameter, which covered with a layer of PS about 7.5‐nm thick and a layer of PAA about 5‐nm thick. This core–shell structure is also conformed by Fourier transform infrared spectroscopy, X‐ray photoelectron spectroscopy, and differential scanning calorimetry. FTIR results show that silica core, PS shell, and PAA outermost shell are bonded by covalents. In the core–shell PAA/PS/SiO₂ hybrid microsphere, the silica core is rigidity, and the PAA outermost shell is polarity, while the PS layer may work as lubricant owning to its superior processing rheological property in polymer blending. These core–shell PAA/PS/SiO₂ hybrid microspheres have potential as new materials for polar polymer modification. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 1729–1733, 2006     

Molecularly imprinted polymer microspheres prepared by precipitation polymerization using a sacrificial covalent bond

Molecularly imprinted polymer microspheres were prepared by precipitation polymerization using a sacrificial covalent bond. In the present model, cholesteryl (4‐vinyl)phenyl carbonate was used as a template monomer. The imprinted microspheres were prepared using ethylene glycol dimethacrylate (EDMA) and divinylbenzene (DVB) as crosslinker. The base‐labile carbonate ester bond was easily hydrolyzed to leave imprinted cavities in the resulting polymers. Radioligand binding analysis, elemental analysis, and scanning electron microscopy were used to characterize the imprinted materials. Imprinted microspheres prepared from DVB crosslinker had larger and more defined spherical shape, and displayed better imprinting effect than did the EDMA‐based microparticles. For comparison, imprinted bulk polymers were also prepared in the same reaction solvent as that used in precipitation polymerization. Elemental analysis results indicated that imprinted microspheres contained more template monomer units than bulk materials. The efficiency of template removal by hydrolysis treatment for microspheres was also higher than that for bulk polymers. For DVB‐based polymers, imprinted microspheres displayed higher specific cholesterol uptake than did the corresponding bulk polymer. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 99: 1390–1398, 2006     

Synthesis,characterization and evaluation of novel methoxypolyethyleneglycol‐ grafted‐ poly(ester‐urethane)s for controlled release of repaglinide

Novel biodegradable aliphatic poly(ester‐urethane)s (PEUs) based on polycaprolactone diol (PCL) and methoxypolyethyleneglycol grafted onto trimethylol propane (mPEG‐g‐TMP) were synthesized by solution polymerization technique and characterized using a variety of techniques. Microspheres ranging in size from 7 to 25 μm were prepared by the solvent evaporation technique and loaded with repaglinide up to 71 to 96%. Increasing molar ratios of mPEG‐g‐TMP propane with respect to polycaprolactone diol gave increase in particle size along with increase in % encapsulation efficiency. Surface morphology and spherical nature of the microspheres were confirmed by scanning electron microscopy (SEM). The release of repaglinide varied, depending upon the molar ratios of mPEG‐g‐TMP moieties with respect to PCL. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

聚丙烯酸和聚苯乙烯磺酸钠调控制备多孔碳酸钙

多孔碳酸钙微球是一种良好的新型缓释载体,在药物缓释、农药控释、涂层防护、橡胶抗老化等领域有广阔的应用前景,合成具有丰富纳米孔道的碳酸钙微球是实现缓释的关键。以氯化钙和碳酸钠为反应原料,选用聚丙烯酸（PAA）为表面活性剂、聚苯乙烯磺酸钠（PSS）为晶型调控剂,通过复分解法制备出球霰石型多孔碳酸钙微球。采用扫描电子显微镜、透射电子显微镜、红外光谱仪、粒度分析仪、比表面及孔隙度分析仪、热重分析仪等手段对获得产物进行表征分析,并研究PAA、PSS浓度对碳酸钙微球形貌和晶型的影响。结果表明,在反应温度为80℃、搅拌速率为600 r/min、PAA和PSS的质量浓度分别为3.0 g/L和3.6 g/L时,可制备出粒径均一、形貌良好、孔隙率较大的多孔碳酸钙微球。     

PCL/poloxamer 188 blend microsphere for paclitaxel delivery: Influence of poloxamer 188 on morphology and drug release

A novel controlled release system, paclitaxel‐loaded poly (ε‐caprolactone) (PCL)/poloxamer 188 (Pluronic F68, F68) blend microspheres is proposed in the present work. F68 was incorporated into PCL matrices as both a pore‐forming agent and a drug releasing enhancer. Paclitaxel‐loaded PCL/F68 blend microspheres with different amounts of F68 were prepared by the oil‐in water (O/W) emulsion/solvent evaporation method. Characterization of the microspheres followed to examine the particle size, the drug encapsulation efficiency, the surface morphology, and in vitro release behavior. The influences of F68 on microsphere morphology and paclitaxel release are discussed. The porosity of the surface of PCL/F68 blend microspheres and the release rate of paclitaxel from the PCL/F68 blend microspheres increased as the initial amount of blended F68 increased. Faster and controlled release was achieved in comparison with the PCL microspheres. Through this study, the developed microporous PCL/F68 blend microspheres could be used as a drug delivery system to enhance and control drug release in the future. © 2007 Wiley Periodicals, Inc. JAppl Polym Sci 104: 1895–1899, 2007     

Preparation and release behavior of carboxymethylated chitosan/alginate microspheres encapsulating bovine serum albumin

Microspheres were prepared from carboxymethylated chitosan (CM‐chitosan) and alginate by emulsion phase separation. Their structure and morphology were characterized with IR spectroscopy and scanning electron microscopy. Bovine serum albumin (BSA) was encapsulated in the microspheres to test the release behavior. The swelling behavior, encapsulation efficiency, and release behavior of BSA from the microspheres at different pHs and with a pH‐gradient condition were investigated. The BSA encapsulation efficiency was calculated to be 80%. The degree of swelling of the microspheres without BSA loaded at pH 7.2 was much higher than that at pH 1.0. The encapsulated BSA was quickly released in a Tris–HCl buffer (pH 7.2), whereas a small amount of BSA was released under acid conditions (pH 1.0) because of the strong electrostatic interaction between ? NH₂ groups of CM‐chitosan and ? COOH groups of alginic acid and a dense structure caused by a Ca²⁺ crosslinked bridge. For the simulation of the processing of the drug under the conditions of the intestine, the microspheres were tested in a pH‐gradient medium, in which an acceleration of the release occurred at pH 7.4 after a lag time at a low pH (5.8–6.8). At pH 7.4, a large amount of BSA was released from the microspheres in a short time because of the rapid swelling of the microspheres. However, the release only depended on the diffusion of BSA at relatively low pHs, this resulted in a relatively low release. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 878–882, 2004     

Investigation on preparation and protein release of biodegradable polymer microspheres as drug‐delivery system

Among the different approaches to achieve protein delivery, the use of polymers, especially biodegraded, holds great promise. This work aimed to study the preparation and protein release of a novel drug‐delivery system based on human serum albumin (HSA) encapsulated into biodegradable polymer microspheres. The microspheres containing HSA were elaborated by the solvent‐extraction method based on the formation of multiple w/o/w emulsion. The encapsulation efficiency (E.E.) of HSA was determined by the CBB method. Alginate/alginate and calcium chloride was added into an internal aqueous phase to investigate the protein loading efficiency, protein stability, and in vitro release profiles. Microspheres were characterized in terms of their morphology, size distribution, loading efficiency, and in vitro protein release. SDS–PAGE results showed that HSA kept its structural integrity during the encapsulation and release procedure. In vitro studies indicated that the microspheres with alginate added in the internal aqueous phase had a smaller extent of burst release. In conclusion, the work presents a new approach for macromolecular drugs (such as protein drugs, vaccines, and peptide drugs) delivery. © 2002 John Wiley & Sons, Inc. J Appl Polym Sci 84: 778–784, 2002; DOI 10.1002/app.10327     

Synthesis and characterization of polyacrylamide‐grafted chitosan hydrogel microspheres for the controlled release of indomethacin

Microspheres of polyacrylamide‐grafted‐chitosan crosslinked with glutaraldehyde were prepared and used to encapsulate indomethacin, a nonsteroidal anti‐inflammatory drug. The microspheres were produced by the water/oil emulsion technique and encapsulation of indomethacin was carried out before crosslinking of the matrix. The extent of crosslinking was analyzed by Fourier transform infrared spectroscopy and differential scanning calorimetry. Microspheres were characterized for drug‐entrapment efficiency, particle size, and water transport into the polymeric matrix as well as for drug‐release kinetics. Scanning electron microscopy confirmed the spherical nature and surface morphology of the particles with a mean particle size of 525 μm. Dynamic swelling experiments suggested that, with an increase in crosslinking, the transport mechanism changed from Fickian to non‐Fickian. The release of indomethacin depends upon the crosslinking of the network and also on the amount of drug loading. This was further supported by the calculation of drug‐diffusion coefficients using the initial time approximation. The drug release in all the formulations followed a non‐Fickian trend and the diffusion was relaxation‐controlled. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 87: 1525–1536, 2003     

Characterization of polyanhydride microsphere degradation by DSC

Microspheres (2.91 μm diameter) were formed from poly(fumaric-co-sebacic anhydride) (P(FASA)) using a phase inversion microencapsulation technique. Blank microspheres, protein-loaded microspheres, and raw polymer were degraded in water for varying lengths of time to determine how degradation affects morphology and crystallinity. The rate of degradation was subsequently characterized using differential scanning calorimetry (DSC) and step-scan alternating DSC (SSADSC). As evident by the changing melting peak ratios during degradation, the protein-loaded microspheres were found to degrade at a more rapid rate than both the blank microspheres and the raw polymer, respectively. This was most likely because the release of protein from the microsphere surface led to an increased surface area available for degradation of this surface-eroding polymer.     

Effect of poly(propylene carbonate) on the crystallization and melting behavior of poly(β‐hydroxybutyrate‐co‐β‐hydroxyvalerate)

The crystallization and melting behavior of poly(β‐hydroxybutyrate‐co‐β‐hydroxyvalerate) (PHBV) and a 30/70 (w/w) PHBV/poly(propylene carbonate) (PPC) blend was investigated with differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR). The transesterification reaction between PHBV and PPC was detected in the melt‐blending process. The interaction between the two macromolecules was confirmed by means of FTIR analysis. During the crystallization process from the melt, the crystallization temperature of the PHBV/PPC blend decreased about 8°C, the melting temperature was depressed by 4°C, and the degree of crystallinity of PHBV in the blend decreased about 9.4%; this was calculated through a comparison of the DSC heating traces for the blend and pure PHBV. These results indicated that imperfect crystals of PHBV formed, crystallization was inhibited, and the crystallization ability of PHBV was weakened in the blend. The equilibrium melting temperatures of PHBV and the 30/70 PHBV/PPC blend isothermally crystallized were 187.1 and 179°C, respectively. The isothermal crystallization kinetics were also studied. The fold surface free energy of the developing crystals of PHBV isothermally crystallized from the melt decreased; however, a depression in the relative degree of crystallization, a reduction of the linear growth rate of the spherulites, and decreases in the equilibrium melting temperature and crystallization capability of PHBV were detected with the addition of PPC. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 2514–2521, 2004     

Study on properties and aggregation structures of deacetylated konjac glucomannan/chitosan hydrochloride absorbent blend gel films

A series of novel blend films of deacetylated konjac glucomannan (d‐KGM) and Chitosan hydrochloride (CHI·HCl) were prepared successfully by using the solvent‐casting technique with different blending ratios of the two polymers. The miscibility and aggregation structure of the blend films were studied by Fourier transform infrared spectroscopy, wide‐angle X‐ray diffraction and scanning electron microscopy. The results indicated that the blend system of d‐KGM and CHI·HCl had a conditional miscibility. A new crystal occurred and hydrogen‐bonding interaction was strengthened when the CHI·HCl content in the blend films was 40%. The effects of deacetylation degree of KGM, acids (the solvent Chitosan dissolved in), temperature, and the mix ratio on the swelling behavior of the blend films were also studied. The blend film KC3 (CHI·HCl content in the blend films was 30%) had not only the highest equilibrium swelling degree (26 times) but also the highest tensile strength, and it could be regarded as a potential absorbent film material. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Molecularly imprinted polymer microspheres with nanopore cavities prepared by precipitation polymerization as new carriers for the sustained release of dipyridamole

Imprinted polymers are now being increasingly considered for active biomedical uses such as drug delivery. In this work, the use of molecularly imprinted polymers (MIPs) in designing new drug delivery devices was studied. Imprinted polymers were prepared from methacrylic acid (MAA) (functional monomer), ethylene glycol dimethacrylate (cross‐linker), and dipyridamole (DIP) (as a drug template) using precipitation polymerization method. The influence of the template/functional monomer proportion and pH on the achievement of MIPs with nanopore cavities with a high enough affinity for the drug was investigated. The small pores (average 3.9 nm) in the imprinted microspheres show excellent retention properties for the target analyte. The polymeric devices were further characterized by FT‐IR, thermogravimetric analysis, scanning electron microscopy, photon correlation spectroscopy, Brunauer‐Emmett‐Teller analysis, and binding experiments. The imprinted polymers showed a higher affinity for DIP and a slower release rate than the nonimprinted polymers. The controlled releases of DIP from the prepared imprinted polymers were investigated by an in vitro dissolution test by measuring the absorbance at 284 nm by means of a UV–Visible spectrophotometer. Loaded imprinted microsphers showed very slow release in various solutions such as phosphate buffer solution (pH 6.8), HCl (pH 1.0) and mixture of HCl and MeOH at 37.0 ± 0.5°C and were able to prolong DIP release for more than two days. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Comparison of micelles formed by amphiphilic poly(ethylene glycol)‐b‐poly(trimethylene carbonate) star block copolymers

In this article, we describe the synthesis and solution properties of PEG‐b‐PTMC star block copolymers via ring‐opening polymerization (ROP) of trimethylene carbonate (TMC) monomer initiated at the hydroxyl end group of the core PEG using HCl Et₂O as a monomer activator. The ROP of TMC was performed to synthesize PEG‐b‐PTMC star block copolymers with one, two, four, and eight arms. The PEG‐b‐PTMC star block copolymers with same ratio of between hydrophobic PTMC and hydrophilic PEG segments were obtained in quantitative yield and exhibited monomodal GPC curves. The amphiphilic PEG‐b‐PTMC star block copolymers formed spherical micelles with a core–shell structure in an aqueous phase. The mean hydrodynamic diameters of the micelles increased from 17 to 194 nm with increasing arm number. As arm number increased, the critical micelle concentration (CMC) of the PEG‐b‐PTMC star block copolymers increased from 3.1 × 10^?3 to 21.1 × 10^?3 mg/mL but the partition equilibrium constant, which is an indicator of the hydrophobicity of the micelles of the PEG‐b‐PTMC star block copolymers in aqueous media, decreased from 4.44 × 10⁴ to 1.34 × 10⁴. In conclusion, we confirmed that the PEG‐b‐PTMC star block copolymers form micelles and, hence, may be potential hydrophobic drug delivery vehicles. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Isothermal crystallization kinetics and melting behaviors of poly(butylene terephthalate) and poly(butylene terephthalate‐co‐fumarate) copolymer

The isothermal crystallization kinetics and melting behaviors after isothermal crystallization of poly(butylene terephthalate) (PBT) and poly(butylene terephthalate‐co‐fumarate) (PBTF) containing 95/5, 90/10, and 80/20 molar ratios of terephthalic acid/fumaric acid were investigated by differential scanning calorimetry. The equilibrium melting temperatures of these polymers were estimated by Hoffman–Weeks equation. So far as the crystallization kinetics was concerned, the Avrami equation was applied and the values of the exponent n for all these polymers are in the range of 2.50–2.96, indicating that the addition of fumarate does not affect the geometric dimension of PBT crystal growth. Crystallization activation energy (ΔE) and nucleation constant (K_g) of PBTF copolymers are higher than that of PBT homopolymer, suggesting that the introduction of fumarate hinders the crystallization of PBT in PBTF. POLYM. ENG. SCI., 2013. © 2012 Society of Plastics Engineers     

Release of diclofenac through gluteraldehyde crosslinked poly(vinyl alcohol)/poly(acrylic acid) alloy membranes

A controlled‐release preparation of diclofenac sodium for transdermal administration has been developed. Poly(vinyl alcohol) (PVA) and PVA/poly(acrylic acid) (PAA) alloy membranes were prepared from a solvent‐casting technique using different PVA/PAA (v/v) ratios. The release of the drug from the membrane was evaluated under in vitro conditions at pH 7.4. The delivery system provided linear release without time lag, burst effect, and boundary layer resistance. Effects of variables such as film thickness and PVA/PAA ratio on the permeation behavior of the polymeric membranes were discussed. The optimal PVA/PAA was determined as 50/50. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 72–77, 2004     

Modification of Nylon 6 by phenol‐containing polymers

A crystalline polymer, Nylon 6, was selectively blended with various amorphous polymers containing phenolic moieties. It was found that moisture absorption by the amide group in Nylon 6 could effectively be reduced by blending with p‐Cl‐novolac at ratios as low as 2 phr (part per hundred resin). Blends of Nylon 6 with vinylphenol homopolymer and its copolymer with styrene also showed reduced moisture uptakes, but the effect was less dramatic than that of the p‐Cl‐novolac blend at all blend ratios. Novolac content in excess of 5 phr shows little additional advantage in moisture reduction. Thermal transitions of blends of Nylon 6 with poly(vinyl phenol), its copolymer, and p‐Cl‐novolac were also investigated. At a blend ratio of 5 phr, p‐Cl‐novolac caused a larger increase in glass transition temperature than the other two blends. The melting temperatures of the blends were little influenced by low levels of the amorphous polymer incorporation, but broader melting endotherms in the differential scanning calorimetry scans were observed. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 73: 295–300, 1999     

Synthesis and characterization of modified chitosan microspheres: Effect of the grafting ratio on the controlled release of nifedipine through microspheres

The grafting of acrylamide onto a chitosan backbone was carried out at three acrylamide concentrations (polymer/monomer ratio = 1:1, 1:2, and 1:3). The synthesis of the grafted polymer was achieved by K₂S₂O₈‐induced free‐radical polymerization. Microspheres of polyacrylamide‐g‐chitosan crosslinked with glutaraldehyde were prepared to encapsulate nifedipine (NFD), a calcium channel blocker and an antihypertensive drug. The microspheres of polyacrylamide‐g‐chitosan were produced by a water‐in‐oil emulsion technique with three different concentrations of glutaraldehyde as the crosslinking agent. Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) were used to characterize the grafted copolymers, and the microspheres were prepared from them. FTIR and DSC were also used to analyze the extent of crosslinking. The microspheres were characterized by the particle size; the water transport into these microspheres, as well as the equilibrium water uptake, were studied. Scanning electron microscopy confirmed the spherical nature of the particles, which had a mean particle size of 450 μm. Individual particle dynamic swelling experiments suggested that with an increase in crosslinking, the transport became case II. The release of NFD depended on the crosslinking of the network and on the amount of drug loading. Calculating the drug diffusion coefficients with the initial time and later time approximation method further supported this. The drug release in all 27 formulations followed case II transport, and this suggested that the time dependence of the NFD release followed zero‐order kinetics. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 2940–2949, 2003