Effect of coating excipients on chemical stability of active coated tablets.

The objective of this study was to understand the impact of coating excipients on the chemical stability of active pan coated peliglitazar, which was prone to acid as well as base-catalyzed degradation. Four different coating formulations containing either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose (HPMC) as a coating polymer and triacetin (glycerol triacetate) or polyethylene glycol (PEG) as a plasticizer/detackifier were used for coating of peliglitazar in a perforated pan coater. Tablets of one-milligram strength were manufactured by suspending the drug in the coating suspension and spray coating onto inert core tablets. The active coated tablets were placed on stability (40 °C/75% RH) in high-density polyethylene (HDPE) bottles in closed condition with desiccants or in open condition. Tablet samples were withdrawn and analyzed for degradants using a stability-indicating HPLC method. The overall stability for the film-forming polymer-plasticizer/detackifier combination showed the rank order: HPMC-triacetin > PVA-triacetin > HPMC-PEG > PVA-PEG. Higher stability of triacetin systems over PEG systems was attributed to lower solubility of peliglitazar in triacetin coating systems. For the same plasticizer/detackifier, higher stability of HPMC over PVA-based formulations was attributed to lower solubility and mobility of peliglitazar in HPMC compared with the PVA-based coating.

Partial tablet coating by 3D printing.

In the last decade 3D printing (3DP) technology has gained increasing interest in the pharmaceutical field addressing several novel challenges such as on-demand manufacturing at the point of need, customization of drug release profiles and patient-specific solutions as well as combinations of several APIs in one dosage form. Therefore, 3DP can become a new and promising path to drug product development and manufacturing, able to support specific therapies and improve compliance, safety and effectiveness. The aim of this work was to partially coat tablets with a glyceride, namely Precirol ATO 5 using a semi-solids 3D printer as an approach for tuning the release of two Active Pharmaceutical Ingredients (APIs), the hydrophilic methyl-levodopa hydrochloride (Melevodopa) and the lipophilic Acyclovir. Various parameters of the 3DP coating process were purposefully modified using experimental design techniques in order to customize the selected APIs release profile, without affecting the core composition of the formulation. The percentage of the tablet surface coated, the number of coating layers as well as the coated sides of the tablet where the parameters which controlled the release profile for both APIs. Different dissolution profiles have been achieved by tuning these simple parameters, which revealed a non-Fickian release mechanism regardless of the API.

Effect of polymer concentration and solution pH on viscosity affecting integrity of a polysaccharide coat of compression coated tablets.

Tablets, compression coated with certain polysaccharides and intended for colon delivery, retain the integrity of the coat for an initial period of about 6 h (lag period) beyond which (post-lag period) the coat is degraded by colonic enzymes to induce drug release. This work was undertaken to investigate the factors which influence the integrity of the coat during the lag period. Core tablets containing two model drugs were compression coated with various amounts of carboxymethyl locust bean gum (CMLBG). In-vitro release of drugs, erosion of coat, and steady shear viscosity of CMLBG solutions having different concentrations and solution pH were determined. The viscosity of CMLBG that depended primarily on CMLBG concentration and partly on solution pH was responsible for erosion and integrity of the coat in the lag period. Evaluation of polymer viscosity could describe the integrity of coat of a polysaccharide coated tablet in the lag period.

Evaluation of in-line Raman data for end-point determination of a coating process: Comparison of Science-Based Calibration, PLS-regression and univariate data analysis.

A multivariate analysis method, Science-Based Calibration (SBC), was used for the first time for endpoint determination of a tablet coating process using Raman data. Two types of tablet cores, placebo and caffeine cores, received a coating suspension comprising a polyvinyl alcohol-polyethylene glycol graft-copolymer and titanium dioxide to a maximum coating thickness of 80µm. Raman spectroscopy was used as in-line PAT tool. The spectra were acquired every minute and correlated to the amount of applied aqueous coating suspension. SBC was compared to another well-known multivariate analysis method, Partial Least Squares-regression (PLS) and a simpler approach, Univariate Data Analysis (UVDA). All developed calibration models had coefficient of determination values (R2) higher than 0.99. The coating endpoints could be predicted with root mean square errors (RMSEP) less than 3.1% of the applied coating suspensions. Compared to PLS and UVDA, SBC proved to be an alternative multivariate calibration method with high predictive power.

Measurement of the Intertablet Coating Uniformity of a Pharmaceutical Pan Coating Process With Combined Terahertz and Optical Coherence Tomography In-Line Sensing.

We present in-line coating thickness measurements acquired simultaneously using 2 independent sensing modalities: terahertz pulsed imaging (TPI) and optical coherence tomography (OCT). Both techniques are sufficiently fast to resolve the coating thickness of individual pharmaceutical tablets in situ during the film coating operation, and both techniques are direct structural imaging techniques that do not require multivariate calibration. The TPI sensor is suitable to measure coatings greater than 50 µm and can penetrate through thick coatings even in the presence of pigments over a wide range of excipients. Due to the long wavelength, terahertz radiation is not affected by scattering from dust within the coater. In contrast, OCT can resolve coating layers as thin as 20 µm and is capable of measuring the intratablet coating uniformity and the intertablet coating thickness distribution within the coating pan. However, the OCT technique is less robust when it comes to the compatibility with excipients, dust, and potentially the maximum coating thickness that can be resolved. Using a custom-built laboratory scale coating unit, the coating thickness measurements were acquired independently by the TPI and OCT sensors throughout a film coating operation. Results of the in-line TPI and OCT measurements were compared against one another and validated with off-line TPI and weight gain measurements. Compared with other process analytical technology sensors, such as near-infrared and Raman spectroscopy, the TPI and OCT sensors can resolve the intertablet thickness distribution based on sampling a significant fraction of the tablet populations in the process. By combining 2 complementary sensing modalities, it was possible to seamlessly monitor the coating process over the range of film thickness from 20 µm to greater than 250 µm.

Setting the process parameters for the coating process in order to assure tablet appearance based on multivariate analysis of prior data.

Designing efficient, robust process parameters in drug product manufacturing is important to assure a drug's critical quality attributes. In this research, an efficient, novel procedure for a coating process parameter setting was developed, which establishes a prediction model for setting suitable input process parameters by utilizing prior manufacturing knowledge for partial least squares regression (PLSR). In the proposed procedure, target values or ranges of the output parameters are first determined, including tablet moisture content, spray mist condition, and mechanical stress on tablets. Following the preparation of predictive models relating input process parameters to corresponding output parameters, optimal input process parameters are determined using these models so that the output parameters hold within the target ranges. In predicting the exhaust air temperature output parameter, which reflects the tablets' moisture content, PLSR was employed based on prior measured data (such as batch records of other products rather than design of experiments), leading to minimal new experiments. The PLSR model was revealed to be more accurate at predicting the exhaust air temperature than a conventional semi-empirical thermodynamic model. A commercial scale verification demonstrated that the proposed process parameter setting procedure enabled assurance of the quality of tablet appearance without any trial-and-error experiments.

Influence of relative humidity during coating on polymer deposition and film formation.

The influence of relative humidity in the pan during coating on polymer deposition and film formation was investigated. Four tablet substrates, differing in hydrophobicity, porosity, and surface roughness, were prepared and coated with Eudragit(®) RS/RL 30 D (8:2 ratio). The spray rate and atomization air pressure were varied to create two distinct micro-environmental conditions in the coating pan. PyroButton data logging devices placed directly in the pan were found to more accurately reflect the relative humidity to which tablets were exposed in comparison to measurements taken at the exhaust. Polymer deposition was shown to be influenced by the properties of the substrate, rather than the processing conditions used during coating, with higher polymer weight gains observed for the more porous tablets. Differences in the film-tablet interface and in the release performance of the coated products, however, were attributed to both the relative humidity in the pan and tablet porosity. Overall, this study demonstrated that a more humid coating process (86% vs 67%) promoted surface dissolution and physical mixing of the tablet ingredients with the forming film and the extent of this phenomenon was dependent on the tablet porosity.

Improving tablet coating robustness by selecting critical process parameters from retrospective data.

CONTEXT: Although tablet coating processes are widely used in the pharmaceutical industry, they often lack adequate robustness. Up-scaling can be challenging as minor changes in parameters can lead to varying quality results. OBJECTIVE: To select critical process parameters (CPP) using retrospective data of a commercial product and to establish a design of experiments (DoE) that would improve the robustness of the coating process. MATERIALS AND METHODS: A retrospective analysis of data from 36 commercial batches. Batches were selected based on the quality results generated during batch release, some of which revealed quality deviations concerning the appearance of the coated tablets. The product is already marketed and belongs to the portfolio of a multinational pharmaceutical company. RESULTS: The Statgraphics 5.1 software was used for data processing to determine critical process parameters in order to propose new working ranges. DISCUSSION AND CONCLUSIONS: This study confirms that it is possible to determine the critical process parameters and create design spaces based on retrospective data of commercial batches. This type of analysis is thus converted into a tool to optimize the robustness of existing processes. Our results show that a design space can be established with minimum investment in experiments, since current commercial batch data are processed statistically.

Preparation and in vitro/in vivo characterization of enteric-coated nanoparticles loaded with the antihypertensive peptide VLPVPR.

Our previous study revealed that the peptide Val-Leu-Pro-Val-Pro-Arg (VLPVPR), which was prepared using deoxyribonucleic acid recombinant technology, effectively decreased the blood pressure of spontaneous hypertensive rats; however, the effect only lasts 6 hours, likely due to its low absorption in the gastrointestinal tract. To overcome this problem, the purpose of this study was to characterize (methoxy-polyethylene glycol)-b-poly(D,L-lactide-co-glycolide)-b-poly(L-lysine) nanoparticles as in vitro and in vivo carriers for the effective delivery of VLPVPR. In our study, the VLPVPR nanoparticles were prepared using a double emulsion method, coated with Eudragit S100, and freeze-dried to produce enteric-coated nanoparticles. The optimized parameters from the double emulsion method was obtained from orthogonal experiments, including drug loading (DL) and encapsulated ratio (ER) at 6.12% and 86.94%, respectively, and the average particle size was below 100 nm. The release experiment demonstrated that the nanoparticles were sensitive to pH: almost completely released at pH 7.4 after 8 hours, but demonstrated much less release at pH 4.5 or pH 1.0 in the same amount of time. Therefore, the nanoparticles are suitable for enteric release. In vivo compared with the untreated group, the medium and high doses of orally administered VLPVPR nanoparticles reduced blood pressure for more than 30 hours, demonstrating that these nanoparticles have long-lasting and significant antihypertensive effects in spontaneously hypertensive rats.

Monitoring of an active coating process for two-layer tablets-model development strategies.

Incorporation of an active pharmaceutical ingredient (API) into the coating layer of film-coated tablets is a method mainly used to formulate combination tablets. Uniform and precise spray coating of an API represents, however, a substantial challenge that could be overcome by applying Raman spectroscopy as process analytical tool. In the present work, active-coating experiments for osmotic-controlled-release oral delivery system (OROS) tablets were performed in a side-vented lab-scale pan coater. During the process, Raman spectra were recorded in-line and off-line after sampling. Quantitative multivariate calibration models were built up by correlating these spectra with the coated API amount at each sampling point. Three different modeling approaches were tested on a second batch with regard to their predictive ability and robustness. By applying the in-line model development approach on OROS tablets, it was possible to overcome the difficulties of this dosage form with each layer contributing differently to the resulting spectroscopic signal and to determine accurately the applied API amount on two-layer tablets. Thereby, the present study demonstrated that Raman spectroscopy can be successfully implemented as a process analytical technology tool to control and monitor an active-coating process of OROS tablets.

A study on in-line tablet coating--the influence of compaction and coating on tablet dimensional changes.

Prior to coating, tablets are usually stored for a definite period to enable complete strain recovery and prevent subsequent volumetric expansion-related coating defects. In-line coating is defined as the coating of tablets immediately after compaction. In-line coating will be expected to improve manufacturing efficiencies. In this study, the possibility of in-line coating was studied by evaluating the influence of compaction and coating on tablet dimensional changes. The use of tapered dies for compaction was also evaluated. Two types of tablet coaters which presented different coating environments, namely the Supercell™ coater and pan coater, were employed for coating. The extent of tablet dimensional changes was studied in real time using optical laser sensors in a controlled environment. After compaction, tablet dimensional changes were found to be anisotropic. In contrast, coating resulted in isotropic volume expansion in both the axial and radial directions. Pan coating resulted in significantly greater tablet dimensional changes compared to Supercell™ coating. There was no significant difference in dimensional changes of tablets coated in line or after complete viscoelastic strain recovery for Supercell™ coating. However, significantly different dimensional changes were observed for pan coating. The use of tapered dies during compaction was found to result in more rapid viscoelastic strain recovery and also significantly reduced tablet dimensional changes when tablets were immediately coated after compaction using the pan coater. In conclusion, the Supercell™ coater appeared to be more suitable for in-line tablet coating, while tapered dies were beneficial in reducing tablet dimensional changes when the pan coater was employed for in-line coating.

Acrylic acid-methyl methacrylate (2.5:7.5/2:8) enteric copolymer for colon targeted drug delivery.

Enteric copolymers of acrylic acid and methyl methacrylate (2.5:7.5 and 2:8) were prepared using tetrahydrofuran as solvent and AIBN as free radical initiator for colon targeting. FTIR and (1)H NMR spectra of the copolymers showed absence of vinyl bond/protons present in the monomers suggesting successful polymerization. Flurbiprofen sodium microspheres (M1 and M2) made with the copolymers, by oil/oil solvent evaporation, were spherical, anionic (zeta potential -57.8 and -53.7 mV) and contained 5.47 and 5.89% drug. FTIR spectrum of microspheres showed peaks for aromatic C = C stretching and substituted benzene ring, indicating entrapment of flurbiprofen. PXRD revealed crystalline structure of flurbiprofen while copolymer and microspheres were amorphous. DSC thermograms showed a sharp melting endotherm of flurbiprofen sodium at 129.26°C against broad endotherms of copolymers and microspheres. The microspheres released 43 and 36% drug at pH 6.8 in 2 h and 99 and 96% at pH 7.4 in next 3-4 h.The microspheres did not adhere on gastric-mucosa at pH 1.2 but showed mucoadhesion time of 18 min and 9 min on intestinal mucosa at pH 6.8. Thus, the microspheres on oral administration, would release the drug in colon, suggesting the potential of the hemocompatible copolymers for pH dependent colon targeted drug delivery system.

Evaluation of the drug release patterns and long term stability of aqueous and organic coated pellets by using blends of enteric and gastrointestinal insoluble polymers.

The major aim of this study was to identify an efficient tool to adjust drug release patterns from aqueous and organic ethylcellulose (a gastrointestinal insoluble polymer) coated pellets and to evaluate the long term stability of the film coatings. Drug release was monitored during open and closed storage at 25 degrees C/60% RH (ambient conditions) and 40 degrees C/75% RH (stress conditions) for up to 24 months. Release of vatalanib succinate, a poorly soluble drug that demonstrates pH-dependent solubility, from pure ethylcellulose coated pellets was slow irrespectively of the type of coating and release medium. By addition of the enteric polymer methacrylic acid/ethyl acrylate copolymer (applied as aqueous Kollicoat MAE 30 DP dispersion or organic solution of Kollicoat MAE 100 P) to ethylcellulose broad ranges of drug release patterns could be achieved. For aqueous film coatings the addition of Kollicoat MAE 30 DP to ethylcellulose dispersions resulted in unaltered drug release kinetics during closed storage at ambient and stress conditions. The storage stabilizing effect of the added enteric polymer might be explained by the more hydrophilic nature of Kollicoat MAE 30 DP compared to ethylcellulose trapping water during film formation and improving polymer particle coalescence. However, during open storage of aqueous coated ethylcellulose:Kollicoat MAE 30 DP pellets at stress conditions drug release decreased due to further gradual polymer particle coalescence. In contrast, drug release rates from organic coated ethylcellulose:Kollicoat MAE 100 P pellets stored at ambient and stress conditions did not change which could be explained by differences in the film formation process. This clearly indicates that the presented concept of the addition of methacrylic acid/ethyl acrylate copolymer to ethylcellulose film coatings in combination with an organic coating process is able to achieve broad ranges of drug release patterns and to overcome storage instability.

Resistant starch as a carrier for oral colon-targeting drug matrix system.

In this study, a novel tablet of protein drug matrix for colon targeting was developed using resistant starch as a carrier prepared by pre-gelatinization and cross-linking of starch. The effects of pre-gelatinization and cross-linking on the swelling and enzymatic degradation of maize starch as well as the release rate of drug from the matrix tablets were examined. Cross-linked pre-gelatinized maize starches were prepared by double modification of pre-gelatinization and cross-linked with POCl(3), and bovine serum albumin was used as a model drug. For in vitro drug release assays, the resistant starch matrix tablets were incubated in simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid, respectively. The content of resistant starch and swelling property of maize starch were increased by pre-gelatinization and cross-linking, which retarded its enzymatic degradation. Drug release studies have shown that the matrix tablets of cross-linked pre-gelatinized maize starch could delivery the drug to the colon. These results indicate that the resistant starch carrier prepared by pre-gelatinization and cross-linking can be used for a potential drug delivery carrier for colon-targeting drug matrix delivery system.

Quantitative analysis of film coating in a pan coater based on in-line sensor measurements.

A method was developed that enables in-line analysis of film coating thickness on tablets during a pan coating operation. Real-time measurements were made using a diffuse-reflectance near-infrared (NIR) probe positioned inside the pan during the coating operation. Real-time spectra of replicate batches were used for modeling film growth. Univariate analysis provided a simple method for in-line monitoring of the coating process using NIR data. An empirical geometric 2-vector volumetric growth model was developed, which accounts for differential growth on the face and band regions of biconvex tablets. The thickness of the film coat was determined by monitoring the decrease of absorption bands characteristic of a component of the tablet core and monitoring the increase of bands characteristic of a component in the coating material. There was good correlation between values estimated from the NIR data and the measured tablet volumetric growth. In-line measurements allow the coating process to be stopped when a predetermined tablet coating thickness is achieved.

The effects of physical parameters on laser-induced breakdown spectroscopy analysis of intact tablets.

With the advent of the Food and Drug Administration initiatives to investigate and encourage the use of process analytical technologies, laser-induced breakdown spectroscopy (LIBS) is considered an excellent analytical tool to understand the processability of solid dosage form. In this article, the feasibility of the LIBS system for quantitation of active drug within a solid dosage form, as well as the effects of various physical parameters on its signal, is investigated. A model drug containing chlorine and sulfur was used. The examination of the specificity and reproducibility of the measurements led to the use of chlorine and carbon as the internal standard. An overall relative SD of 1.1% for the signal was found. For quantitation purposes, calibration curves using compound-X in formulated tablets were generated. It was found that curves generated from roller-compaction tablets generally gave higher LIBS signal than those generated using direct-compressed (DC) process. To investigate these differences, effect of LIBS signals from several physical properties of the tablets were examined. It was found that unmilled compound-X used in the manufacture of the tablets gave a LIBS signal 30% lower than when milled compound-X was used. However, by using multiple crushing-recompression DC process of the milled compound-X, the LIBS results were comparable with those found from both processed tablets using milled compound-X. Other physical parameters, such as wide ranges of granule size and tablet hardness found in the typical manufacturing process, had limited effect on the LIBS signal. From these results, it was noted that for accurate quantitation, it is necessary to use the same physical properties of compound-X and the same manufacturing process in the calibration standards as the actual samples.

Production of enteric capsules by means of hot-melt extrusion.

The aim of this study was to develop an alternative technique for enteric coating consisting of the hot-melt extrusion of coating polymers. An enteric coating polymer (PVAP or HPMC AS), premixed with a plasticizer, was extruded into hollow cylinders. The hollow pipes were filled with a model drug and both open ends of the cylinders were closed, yielding hot-melt extruded enteric capsules. Main advantages of this new technology are the continuity of the process and its application for the formulation of moisture sensitive active ingredients. The enteric capsules showed excellent gastro-resistance, since no drug release was observed after 2 h 0.1N HCl. The influence of wall thickness (0.15, 0.3, 0.5, 0.8, and 1.0 mm) of the capsules on drug release was investigated. Enteric capsules with a wall thickness of 1.0 mm were subjected to a pH gradient dissolution method, simulating passage through the gastro-intestinal tract, in order to evaluate their suitability for ileal or colonic drug targeting. Storing the capsules for 1 month at high relative humidity (RH) (60 and 75% RH) revealed that the HPMC AS capsules were superior to the PVAP capsules. It can be concluded that hot-melt extruded capsules seem suitable as an alternative for enteric coating.

Development of enteric-coated timed-release matrix tablets for colon targeting.

A new oral drug delivery system for colon targeting has been developed based on enteric-coated matrix tablets which suitably exploits both pH-sensitive and time-dependent functions. Matrix-tablets were prepared by direct compression of mixtures of hydroxyethylcellulose (HEC), a hydrophilic swellable polymer, with the inert insoluble ethylcellulose (EC) or micro-crystalline cellulose (MCC) polymers, in which theophylline, selected as model drug, was dispersed. Eudragit S100, a methacrylic acid copolymer soluble at pH 7, was used as pH-sensitive coating polymer. The influence of varying the cellulose-derivative combinations and their relative ratios as well as the level of the coating polymer was investigated. Surface morphology of the tablets was monitored by SEM analysis before and after the release test. The results of release studies, performed according to the USP basket method using a sequence of dissolution media simulating the gastrointestinal physiological pH variation, indicated that the Eudragit S100 enteric-coated matrix tablets were successful in achieving gastric resistance and timed-release of the drug, assuring an adequate lag time for the intended colonic targeting, followed by a controlled-release phase. The enteric-coating level emerged as the critical factor in determining the duration of the lag-phase, whereas the release rate mainly depended on the matrix composition. Formulations with higher HEC content showed a faster drug release rate than those with greater content in inert polymer and the MCC-HEC combinations were more effective than the corresponding EC-HEC ones. The best results were given by the 27% coated 1:0.3:0.7 (w/w) drug/MCC/HEC tablets, which, after a 260 min lag time, regularly released the drug, achieving about 90% of release after 10 h.

Temperature/Humidity sensitivity of sustained-release formulations containing Kollidon SR.

The effects of temperature and humidity on tablets containing Kollidon SR have been evaluated using diphenhydramine HCl as a model drug. Exposure of tablets to ICH accelerated stability condition (40 degrees C/75%RH) in an open dish resulted in rapid increases in tablet hardness, accompahied by step-wise decreases in dissolution rate. Such a change can be observed as fast as an hour upon exposure. The tablet matrix appears to rapidly absorb atmospheric moisture, as demonstrated by tablet weight gain and moisture adsorption isotherms. Exposure to 25 degrees C/60%RH similarly resulted in increases in tablet hardness, although with minimal impact on dissolution. Potential implications of such rapid moisture uptake during aqueous film-coating were further evaluated by spraying either water or an Opadry solution in a coating pan. Exposure of Kollidon SR tablets to the aqueous coating process indeed resulted in noticeable changes in both hardness and dissolution. Application of the Opadry solution appears to affect tablet behavior to a lesser degree, compared to water, most likely due to protection via formed barrier film. Attention needs to be paid to the extreme sensitivity of Kollidon SR matrix tablets to temperature and moisture during product development.

A novel amylose corn-starch dispersion as an aqueous film coating for tablets.

A novel aqueous coating dispersion of amylose-rich corn starch (Hylon VII) was evaluated in an aqueous film-coating process of tablets using an instrumented laboratory-scale pan-coating apparatus. The influence of two independent process variables, the coating temperature and the atomizing air pressure, on the properties of the coated tablets were investigated. The preuse stability of aqueous coating dispersion (i.e., amylose corn-starch precipitate) was studied using a powder X-ray diffraction (XRD) technique. The crystallinity of amylose starch in the coating dispersion was found to increase slightly during 9 months of storage (in a refrigerator 6 +/- 2 degrees C). The film coatings of an aqueous amylose-rich starch dispersion were successfully applied onto tablets without any significant drawbacks, such as nozzle blockage or related problems. It was found that the temperature in the coating pan had a significant influence on the film surface roughness, mechanical strength, and drug release in vitro. When the lowest coating temperature (30 degrees C) was used, rougher film coatings were obtained due to overwetting. At higher temperatures (up to 50-60 degrees C), lower surface roughness and higher mechanical strength values for the coated tablets were obtained. With the present amylose starch dispersion, the atomizing air pressure had a minor influence on the quality of the coating. Under appropriate coating conditions, a smooth tablet film coating was produced with this new, natural, and inexpensive amylose starch dispersion.