Understanding the thermodynamic micro-environment inside a pan coater using a data logging device

Objective: The objective of the current study was to establish the use of PyroButton data-logging device to monitor and quantify the thermodynamic environment (temperature and humidity) of a pan coating process.

Material and methods: PyroButtons were placed (fixed) at various locations in a pan coater, including exhaust plenum, spray-gun bar, baffles and were also allowed to freely move with the tablet-bed. A full factorial design of experiments (DOE) study on three process parameters, exhaust temperature, pan speed and spray rate was conducted on a 24 inch pan coater, using a coating system and a core tablet combination expected to have a narrow process operating space.

Results: It was shown that the PyroButtons can provide a detailed and useful signature of the coating process. PyroButton data showed that the tablet-bed temperature was always lower than exhaust temperature and that the difference was a function of the operating conditions such as spray rate. Similarly, the tablet-bed humidity was found to always be higher than exhaust humidity. Some of the DOE batches showed coating defects (logo-bridging). It was shown that the relative humidity (RH), as measured by the freely-moving PyroButtons in the tablet-bed, correlated well with the logo-bridging events. A critical RH value (30%) was established, above which logo-bridging was observed for the selected formulation.

Conclusions: This study showed that PyroButtons can provide very meaningful micro-environmental data that can be correlated to coating defects, and can aid in establishing a process design space for a given coating and tablet formulation.     

Effect of Aqueous Film Coating Conditions on Water Removal Efficiency and Physical Properties of Coated Tablet Cores Containing Superdisintegrants

Abstract

Few studies have examined the effect of aqueous film coating process conditions on the physical integrity of the final coated product. Characterization of the aqueous film coating process was previously carried out by selecting water removal efficiency as the response variable to detect and monitor moisture accumulation in the tablet bed [1]. In this study, regression techniques were utilized to obtain the relationship between some physical characteristics of aqueous film coated tablet cores that contained superdisintegrant and several process parameters such as inlet air temperature, spray rate, and pan speed. Tablet response variables measured included residual moisture content, tensile strength and percent porosity. Predicted values of these properties were plotted as a function of the inlet air temperature and the coating solution spray rate. The correlations between the coated tablet response variables and the water removal efficiency of the coating process indicated that coated tablet properties such as residual moisture content, tensile strength, and porosity were linearly correlated with the water removal efficiency of the coating process, which is indicative of the environmental coating conditions present in the coating pan.     

The Solubilization of Drug and Excipient Into a Hydroxypropyl Methylcellulose (HPMC)-Based Film Coating as a Function for the Coating Parameters in a 24” Accela-Cota®

Abstract

During the aqueous film coating of tablets, components of tablets tend to migrate to the film coating. This migration is enhanced if a component is soluble in the coating solution and also depends on the spray condition used during the coating operation. In this study, a 2³ orthogonal factorial design was used to study the migration of drug and stearic acid from a tablet to an aqueous-based cellulose coating solution. The independent variables evaluated were atomization air pressure, inlet air temperature, and spray rate. Differential scanning calorimetry was used to quantitate the presence of guaifenesin and stearic acid in the film coating. In the 24″ Accela Cota that was used on our experiment, only spray rate and inlet air temperature influenced the migration of drug and stearic acid the film coating.     

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°C/75%RH) in an open dish resulted in rapid increases in tablet hardness, accompanied 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°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.     

The miniwid-coater: I. design and evaluation of a temperature-controlled miniature fluid-bed pan coater

Abstract

A novel miniature laboratory-scale pan coater has been developed. Small batches of 50 to 100 g of pellets, granules, large crystalls and small tablets allow the formulation development with minimal quantities of valuable drugs and new active ingredients. Although originally it is a pan coater, the core bed will be slightly fluidized by the inlet air flow due to the small dimensions of the coating pan. This allows a rapid drying and the loss of coating materials will be negligible.

A computer was used to control the core bed temperature during the coating process by varying the spraying rate of an analytical dosing pump. Additionally, the drying air temperature can be adopted. It was possible to change the parameters during the process to optimize the operation conditions within one run. The computer program described in this article provides a constant bed temperature with a precision of ± 0.3 °C.

In the MiniWiD-Coater, neutral pellets have been loaded with bisacodyl and then enteric-coated with aqueous dispersions of Eudragit L 30 D. Batch homogeneity and reproducibility were excellent. Friability of the cores and abrasion of the coat remained low. The loss of coating material during operation was always below 5 %.     

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°C/75%RH) in an open dish resulted in rapid increases in tablet hardness, accompanied 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°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.     

Effect of Aqueous Film Coating Conditions on Water Removal Efficiency and Physical Properties of Coated Tablet Cores Containing Superdisintegrants

Few studies have examined the effect of aqueous film coating process conditions on the physical integrity of the final coated product. Characterization of the aqueous film coating process was previously carried out by selecting water removal efficiency as the response variable to detect and monitor moisture accumulation in the tablet bed [1]. In this study, regression techniques were utilized to obtain the relationship between some physical characteristics of aqueous film coated tablet cores that contained superdisintegrant and several process parameters such as inlet air temperature, spray rate, and pan speed. Tablet response variables measured included residual moisture content, tensile strength and percent porosity. Predicted values of these properties were plotted as a function of the inlet air temperature and the coating solution spray rate. The correlations between the coated tablet response variables and the water removal efficiency of the coating process indicated that coated tablet properties such as residual moisture content, tensile strength, and porosity were linearly correlated with the water removal efficiency of the coating process, which is indicative of the environmental coating conditions present in the coating pan.     

Physical Properties and Stability of Diazepam and Phenobarbitone Sodium Tablets Prepared with Compactrol

Abstract

Compactrol as a newly introduced direct compressible vehicle was used for the preparation of Diazepam and phenobarbitone sodium tablets. Spray dried lactose and wet granulation technique were also employed to prepare these tablets for comparison. The effect of storage at 75% RH, at two temperature levels (25° and 45°) on the physical properties of these tablets was studied for 6 weeks. It was found that, there were an increase in tablet weight, thickness and friability per cent, while a significant decrease in hardness was observed. Tablets prepared with compactrol showed no significant changes in both disintegration and dissolution times, while tablets prepared with spray dried lactose showed a marked decrease in disintegration and dissolution times. On the other hand, tablets prepared by wet granulation showed a pronounced in crease in both disintegration and dissolution times.     

Implementation of quality by design approach in manufacturing process optimization of dry granulated,immediate release,coated tablets – a case study

The aim of this study was to optimize the process of tablets compression and identification of film-coating critical process parameters (CPPs) affecting critical quality attributes (CQAs) using quality by design (QbD) approach. Design of experiment (DOE) and regression methods were employed to investigate hardness, disintegration time, and thickness of uncoated tablets depending on slugging and tableting compression force (CPPs). Plackett–Burman experimental design was applied to identify critical coating process parameters among selected ones that is: drying and preheating time, atomization air pressure, spray rate, air volume, inlet air temperature, and drum pressure that may influence the hardness and disintegration time of coated tablets. As a result of the research, design space was established to facilitate an in-depth understanding of existing relationship between CPPs and CQAs of intermediate product (uncoated tablets). Screening revealed that spray rate and inlet air temperature are two most important factors that affect the hardness of coated tablets. Simultaneously, none of the tested coating factors have influence on disintegration time. The observation was confirmed by conducting film coating of pilot size batches.     

The Effect of Moisture Sorption and Desorption on Furosemide Tablet Properties

Abstract

The effect of moisture sorption and desorption on the physical characteristics of furosemide tablet was studied at moderately elevated temperatures and different relative humidity conditions over 20 days. The rate of moisture sorption and desorption was founud to follow first order kifietics within first hours. Except ambient conditions (RT/Amb.RH), moisture sorption caused a decrease in hardness values of furosemide tablets. Also the disintegration times of hydrated tablets showed a remarkeable decrease. Changes in hardness and disintegration time were dependent on the amount of water sorbed into the tablets. These significant changes occured during the first days of the test and then became invariant. The variations in hardness and disintegration times of tablets were irreversible as demonstrated by desorption experiments.

Furthermore, except storage at high temperature and high relative humidity dissolution parameters of tablets were less affected by moisture sorption and desorption.     

Evaluation of performance of co crystals of mefloquine hydrochloride in tablet dosage form

Objective: The objective of present investigation was to evaluate performance of cocrystals of Mefloquine Hydrochloride (MFL) in tablet dosage form. Our previous investigation showed significant effect of cocrystal formers on improving the solubility and dissolution rate of Mefloquine hydrochloride by cocrystallization method when prepared by solution cocrystallization method.

Materials and methods: Prepared cocrystals of MFL with different ratio of cocrystal formers were incorporated in tablet dosage form and evaluated for micrometric properties, drug content, hardness, disintegration test, vitro dissolution studies and stability studies. Performance was compared with laboratory prepared tablet of MFL 250 mg.

Results: The considerable improvement in the dissolution rate was observed in case of cocrystals based tablets than pure MFL tablets.

Discussion and conclusion: So we can incorporate cocrystals in tablet dosage form to enhance in vitro and in vivo performance. To the best of our knowledge, this is the first report, cocrystals has been evaluated in tablet dosage form.     

Application of Simplex and Statistical Analysis for Correction of Pitting in Aqueous Film Coated Tablets

Pitting or pin hole formation is a tablet defect that is commonly observed in aqueous film coated tablets containing highly moisture-sensitive materials. It is generally believed that pitting is due to dissolution of soluble particles on the tablet surface when the tablet is overwetted during the coating process. An experiment was conducted to study the effects of spray rate and pan speed, the two important factors contributing to this condition. The data thus obtained were analyzed by using the simplex search procedure and the appropriate statistical methods. The levels of the two factors that minimized pitting were achieved as a result of the analysis.     

Continuous direct tablet compression: effects of impeller rotation rate,total feed rate and drug content on the tablet properties and drug release

Context: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages.

Objective: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process.

Materials and methods: The tablet formulations consisted of acetaminophen (3–30% (w/w)) pre-blended with 0.25% (w/w) colloidal silicon dioxide, microcrystalline cellulose (69–96% (w/w)) and magnesium stearate (1% (w/w)). The continuous tableting line consisted of three loss-in-weight feeders and a convective continuous mixer and a rotary tablet press. The process continued for 8?min and steady state was reached within 5?min. The effects of acetaminophen content, impeller rotation rate (39–254?rpm) and total feed rate (15 and 20?kg/h) on tablet properties were examined.

Results and discussion: All the tablets complied with the friability requirements of European Pharmacopoeia and rapidly released acetaminophen. However, the relative standard deviation of acetaminophen content (10% (w/w)) increased with an increase in impeller rotation rate at a constant total feed rate (20?kg/h). A compression force of 12?kN tended to result in greater tablet hardness and subsequently a slower initial acetaminophen release from tablets when compared with those made with the compression force of about 8?kN.

Conclusions: In conclusion, tablets could be successfully prepared by a continuous direct compression process and process conditions affected to some extent tablet properties.     

Press Chamber Coating as External Lubrication for High Speed Rotary Presses: Lubricant Spray Rate Optimization

ABSTRACT

Lubrication of the tooling (punches and dies) is necessary to produce tablets. The most commonly used lubricant is magnesium stearate. Adding and blending magnesium stearate to the tablet mass often has negative effects on the properties of the compressed tablets (e.g., decreasing the tensile strength of the tablet). To avoid these negative effects, external lubrication systems were developed. This study investigated the functionality and the influence of a new press chamber coating system called the PKB II. The major difference between the PKB II and previous systems is its ability to spray a mixture of powdered magnesium stearate and air directly onto the punches and dies which was determined to allow the running of the rotor at higher speeds. The data showed a clear correlation between the spray rate of the lubricant and the concentration of the magnesium stearate per tablet. The PKB II was designed to allow for adjustments, in order to optimize the spray rate, by using the ejection force. The concentration of magnesium stearate was reduced to approximately 0.04% per tablet, using the PKB II. Additionally, the most common negative effects, such as the decrease in tablet tensile strength, were avoided by using this system.     

Quality-by-design approach for the development of telmisartan potassium tablets

A quality-by-design approach was adopted to develop telmisartan potassium (TP) tablets, which were bioequivalent with the commercially available Micardis^® (telmisartan free base) tablets. The dissolution pattern and impurity profile of TP tablets differed from those of Micardis^® tablets because telmisartan free base is poorly soluble in water. After identifying the quality target product profile and critical quality attributes (CQAs), drug dissolution, and impurities were predicted to be risky CQAs. To determine the exact range and cause of risks, we used the risk assessment (RA) tools, preliminary hazard analysis and failure mode and effect analysis to determine the parameters affecting drug dissolution, impurities, and formulation. The range of the design space was optimized using the face-centered central composite design among the design of experiment (DOE) methods. The binder, disintegrant, and kneading time in the wet granulation were identified as X values affecting Y values (disintegration, hardness, friability, dissolution, and impurities). After determining the design space with the desired Y values, the TP tablets were formulated and their dissolution pattern was compared with that of the reference tablet. The selected TP tablet formulated using design space showed a similar dissolution to that of Micardis^® tablets at pH 7.5. The QbD approach TP tablet was bioequivalent to Micardis^® tablets in beagle dogs.     

Storage Related Physico-Chemical Changes in Aspirin and Phenylbutazone Tablets Compressed With Different Initial Moisture Content

Abstract

The storage conditions as well as the compressional conditions of the aged tablets were found to have significant effect on their physico-chemical properties. In this study the changes in tablet weight, thickness, hardness, disintegration, drug release and drug content were evaluated for aspirin and phenylbutazone (pbz) tablets made with microcrystalline cellulose (MCC) and lactose bases. Tablets were made with different initial moisture content and stored at 40°C/90% relative humidity (R.H.). Tablet thickness was found, in general, to increase with storage, this increase was more prominent with aspirin. The increase in thickness was always accompanied with a decrease in hardness. There was a marked increase in disintegration time and decrease in dissolution rate of phenylbutazone tablets. This was more significant for the lactose based tablets, while, for aspirin tablets there was a negligible increase in both dissolution rate and the disintegration time. The present study indicated that incorporation of drugs in tablet bases has resulted in a different response towards storage     

Development of delayed-release proliposomes tablets for oral protein drug delivery

Context: One among many attempts to improve oral protein drug delivery was utilizing the colloidal drug carriers particularly liposomes.

Objective: The purpose was to develop proliposomes of bovine serum albumin (BSA) in the form of granules and delayed-release tablets by using simple tablet manufacturing process.

Materials and methods: BSA proliposomes granules were prepared by spraying 7:3 (w/w) – lecithin:cholesterol solution mixture onto BSA-mannitol granules rotating in a glass coating pan. BSA proliposomes granules were directly compressed into tablets and subsequently coated with Eudragit^® L100 film. The physical properties and stability in gastrointestinal fluids of delayed-release BSA proliposomes tablets as well as reconstituted liposomes were assessed.

Results: The BSA proliposomes tablets disintegrated readily and the obtained reconstituted BSA liposomes exhibited multilamellar vesicles, the size and entrapment efficiency of which were around 2–3 µm and 10–14%, respectively. The delayed-release BSA proliposomes tablets were found to be relatively stable in United States Pharmacopoeia (USP) simulated gastric and intestinal fluids. Increase in amount of BSA in granules resulted in the increase in entrapment efficiency and loading capacity.

Discussion: The Fourier transform infrared spectroscopy (FTIR) results indicated increase in α-helix structure of BSA entrapped in liposomes. ³¹P phosphorous nuclear magnetic resonance spectroscopy (³¹P-NMR) spectrum indicated interaction between BSA molecules and phosphoric acid polar groups of bilayers membrane.

Conclusion: The delayed-release BSA proliposomes tablets developed could completely be reconstituted into liposomes with sufficient resistance to the hostile environment in gastrointestinal tract.     

Effects of tablet core dimensional instability on the generation of internal stresses within film coats part II: Temperature and relative humidity variation within a tablet bed during aqueous film coating in an accela-cota

Abstract

Temperature and relative humidity variations within a tablet bed were measured during a complete typical aqueous film coating procedure in an Accela-Cota Model 10. Characteristic thermal and moisture patterns on which it was possible to distinguish the stages of coating process were obtained. Inlet air temperature as a processing variable and different locations within the tablet bed were found to influence these patterns significantly.     

Water Soluble Cellulose Acetate: A Versatile Polymer for Film Coating

ABSTRACT

The objective of this study was to investigate the use of water soluble cellulose acetate (WSCA) as a film coating material for tablets. Aspirin (ASA) tablets were prepared by direct compression and coated with either WSCA or HPMC (hydroxypropyl methylcellulose) dispersions. Coatings of 1–3%, depending on the intended application, were applied to the model drug (ASA) tablets employing a side-vented coating pan. Free films of WSCA, prepared by cast method, are crystal clear and, depending on the viscosity grade, are flexible, strong and durable. WSCA has the capability of forming free films without plasticizers and the films dry at room temperature. Glass transition temperature, Tg, was determined by differential scanning calorimetry. The Tg of WSCA is significantly higher relative to HPMC. Inclusion of plasticizer lowers the Tg of WSCA and effective plasticizers were PEG 400 and glycerin. Low viscosity WSCA was more soluble in water (25–30%) relative to medium viscosity WSCA (10–15%). WSCA solutions exhibited no increase in viscosity with an increase in temperature. Samples of coated (WSCA and HPMC) tablets and uncoated ASA cores were packaged for stability studies at room and elevated temperature storage. Physical stability of ASA tablets coated with 2:1 LV: MV (low viscosity: medium viscosity) WSCA formulations was better when compared to tablets coated with HPMC. Dissolution stability of WSCA coated ASA was similar to the physical stability results. After three months at elevated temperature (35 and 45°C), the WSCA coated tablets complied with USP dissolution requirements for ASA, while the HPMC coated tablets did not. There was no difference in moisture (weight) gain of ASA tablets coated with either WSCA or HPMC. The WSCA coated tablets were not sticky or tacky, while the HPMC coated tablets were tacky and stuck together.     

Investigation into The Yellowing on Aging of Sabril® Tablet Cores

Abstract

Uncoated Sabril® tablet cores under long term storage become slightly discolored from the initial white to a yellowish off-white color. In order to ensure the aesthetics of the product, Sabril tablet cores are film coated with an opaque white coating. The nature of this yellowing reaction was of interest even though discolored tablets showed no significant loss of potency on assay. Excipient compatibility studies showed that the vigabatrin active in Sabril mixed with Avicel (microcrystalline cellulose) in the presence of moisture also became off-colored when stressed at elevated temperatures.

The nature of the discoloration in aged Sabril core tablets was investigated. Chromatographic and spectroscopic data indicate that the source of this color comes from the Maillard Reaction between vigabatrin and Avicel which results in a multitude of products analogous to “browning reactions” of food products. A gravimetric determination of the leached colored products from 7 year old Sabril core tablets gave a residue of less than 0.1% relative to vigabatrin. Furthermore, based on spectroscopy, most of this residue was found to be povidone, an excipient in the tablets which was isolated along with the colored substances.

Therefore, the colored products identified in the core of Sabril tablets stored for an extended period of time represent only minor impurities. Their formation through aging arises via the Maillard Reaction and would only constitute a matter of aesthetics. The latter problem is avoided by the currently employed film coating process.

Similar reactions could be predicted for other drugs having amine functional groups if they are formulated with microcrystalline cellulose or reducing sugars.