Pulmonary drug delivery with aerogels: engineering of alginate and alginate-hyaluronic acid microspheres.

In this study, the aerogel technology was used to prepare pulmonary drug carriers consisting of alginate and alginate-hyaluronic acid by an emulsion gelation technique and supercritical CO2 drying. During the preparation process, the emulsification rate and inner phase viscosity were varied to control the diameter of aerogel microspheres. Results showed that the aerogel microspheres were highly porous (porosity > 98%) with low densities in the range between 0.0087 and 0.0634 g/cm3 as well as high surface areas between 354 and 759 m2/g. The obtained microspheres showed aerodynamic diameter below 5 µm making them suitable for pulmonary drug delivery. An in vitro drug release study with the model drug sodium naproxen was conducted and a non-Fickian drug release mechanism was observed, with no significant difference between the release profiles of alginate and alginate-hyaluronic acid microspheres. During the emulsion gelation step, the feasibility of using the capillary number to estimate the largest stable droplet size in the emulsions was also studied and it was found that using this number, the droplet size in the emulsions may well be predicted.

Application of Externally Applied Lower Punch Vibration and its Effects on Tablet Manufacturing.

PURPOSE: In the present study the influence and application of a newly developed external lower punch vibration system for an improved die filling on a running rotary tablet press was investigated. METHODS: Tablets were manufactured at different conditions (with and without vibration) and characterized regarding their direct compressibility and mechanical stability. Thus, two typical pharmaceutical binders for direct compression (Parmcel 102 and Tablettose® 80) were compared with two binders unsuitable for direct compression (Ceolus® KG1000 and GranuLac® 200). The powders were characterized by helium pycnometry, laser diffraction, scanning electron microscopy, and by determination of the powder flow. Furthermore, a novel technique to determine the occurrences of segregation within a tablet after manufacturing was introduced. For this purpose, a powder blend containing one spray-colored type of microcrystalline cellulose (Vivapur® 200) were prepared. RESULTS: It was shown that under application of externally applied lower punch vibration, the powder flow into the die increased and thus the die filling process was significantly improved. Hence, it was possible to manufacture tablets from powders, which are actually unsuitable for direct compression. In addition, the mechanical stability of the produced tablets was distinctly improved by application of lower punch vibration, whereby the occurrence of segregation was comparatively low. CONCLUSION: In summary, lower punch vibration allows a more efficient die filling, whereby the powder flow as well as mechanical stability of the tablets are improved.

Comparison of two paddle wheel geometries within the filling chamber of a rotary tablet press feed frame with regard to the distribution behavior of a model powder and the influence on the resulting tablet mass.

Objective: The purpose of this study was to compare the influence of two different paddle wheel geometries on the distribution behavior of a model powder within the filling chamber of the modified feed frame of a rotary tablet press. Moreover, both paddle wheels were compared regarding their influence on the resulting tablet mass during the tableting process. Significance: Insights are provided regarding the influence of the paddle wheel geometry on the powder distribution to optimize the die filling process. Materials and methods: Avicel PH 102 served as model powder. A laser triangulator was used to scan the powder surface level within the feed frame and, combined with the determination of the angle position of the paddle wheel, an in-house written software was used to calculate the powder surface profiles and filling levels. Two experimental setups, one based on the filling chamber filled with a defined amount of powder (offline) and one using the filling chamber during tableting (inline) were applied. Results: Both paddle wheel geometries caused a significantly different distribution behavior of the powder within the filling chamber. The tablets obtained with the round rod filling wheel showed significantly higher tablet masses and significantly lower standard deviations. The inflow of powder into the filling chamber appeared to be improved with the round rod filling wheel. Conclusions: Under the applied experimental conditions, the round rod filling wheel showed obvious advantages compared to that with flat rods in terms of the uniformity of tablet masses and the extent of die filling.

Combination of a hot-melt subcoating and an enteric coating for moisture protection of hygroscopic Sennae fructus tablets.

The objective of this study was to investigate the efficiency of moisture protection of hot-melt coatings solely and in combination with an enteric coating on hygroscopic tablet cores containing a spray-dried Sennae fructus extract. Tablet cores were subcoated with different hot-melt coating materials: medium chain tryglycerides, stearic acid, Precirol® ATO 5, and Compritol® 888 ATO, at varying amounts and coated with Eudragit® L 30D-55 for enteric resistance. Subcoating penetration, tablet disintegration, dissolution times, tablet hygroscopicity, and tablet properties such as weight, height, diameter, and hardness were analyzed. 3 mg/cm2 of tablet surface seemed to be sufficient if sustained release is not required. Thereby, hot-melt coating did not adversely affect the tablet properties with regard to subsequent processing steps. Compared to the tablet cores it was possible to reduce the moisture uptake by 85% at 75% relative humidity with tablets coated with a combination of Precirol® ATO 5 and Eudragit® L 30D-55. This combination was more efficient than high amounts of Eudragit® L 30D-55. Hot-melt coating proved to be a suitable technique for the application of subcoating material to tablet cores serving as a barrier against water permeation into hygroscopic tablet cores without exceeding the required disintegration times.

Performance Characteristics of a Novel Vibration Technique for the Densification of a Powder Bed within a Die of a Rotary Tablet Press - a Proof of Concept.

The aim of this study was to investigate the concept of lower punch vibration as a possible approach to densify the powder bed within the die of a rotary tablet press. Therefore, a laboratory vibration equipment was developed to obtain a better understanding of the performance characteristics and effects of a pneumatically generated vibration system on pharmaceutical powders. For this purpose, two widely used pharmaceutical powders, basic magnesium carbonate (Pharmagnesia MC Type F) and microcrystalline cellulose (Ceolus® KG1000), both with different physical properties, were investigated. The powders were characterized by laser diffraction, scanning electron microscopy, helium pycnometry, ring shear testing, gas adsorption, and by determination of the powder flowability. Furthermore, the extent of densification within the die during vibration was visualized by a high-speed camera system and analyzed by an image-analyzing software. It was observed that lower punch vibration was able to densify the powder bed to a sufficient extent and within an adequate time period. Consequently, the presented results revealed that lower punch vibration may be a promising technique to remove entrapped air from powder beds, thus obtaining a denser powder bed within the die, which might potentially improve the tableting process and prevent complications during tablet manufacture.

Investigation of the tableting behavior of Ibuprofen DC 85 W.

The aim of the present study was to investigate the tableting behavior of Ibuprofen DC 85 W with special focus on the tablet disintegration time, the tablet crushing strength, and the sticking tendency to punch surfaces. To simulate production conditions, tableting was conducted on a rotary press, equipped with three compaction stations. An I-optimal design of experiments was used to analyze the influence of the pre-compaction, the intermediate compaction, and the main compaction force on the two responses: tablet disintegration time and crushing strength. It was shown that Ibuprofen DC 85 W showed a good tableting behavior with regard to both responses. The tablet disintegration was considerably affected by the maximum compaction force applied, but was also slightly affected by preceding compaction events. The tablet crushing strength was mainly affected by the maximum applied compaction force independent of the order of these forces. The sticking tendency of Ibuprofen DC 85 W was compared with that two other ibuprofen powder formulations in long-term tableting runs. Compared to the other two formulations, sticking was considerably lower with Ibuprofen DC 85 W. The sticking tendency was not influenced by the addition of an intermediate compaction force, but was remarkably reduced by the choice of the punch tip coating.

Factors influencing the properties and the stability of spray-dried Sennae fructus extracts.

OBJECTIVE: The objective of this study was to characterize the properties of aqueous Sennae fructus extracts prepared by spray-drying at varying process conditions. SIGNIFICANCE: From an industrial point of view it is essential to develop a formulation which has a constant quality over the whole period of its specified shelf-life. METHOD: Sennae fructus extracts were spray-dried with different atomizing gas pressures, pump feed rates, and inlet temperatures. The extracts were analyzed for their physical properties and stored at accelerated conditions. Sennoside degradation was monitored by HPLC analysis. RESULTS: An increase of the atomizing gas pressure had the most pronounced influence on the decrease of moisture content and particle size. An increase of the inlet temperature led to a decrease of moisture content and particle density, as well as an increase of smooth particle amount. An increase in the pump feed rate, increased the moisture content and resulted in stable hollow spheres. The different conditions also led to smooth or wrinkled particle surfaces, and to golfball, donut, and shard particle shapes. The chemical stability of the sennosides differed from each other after storage. Stability-reducing factors were the moisture content of the samples and their hygroscopicities, as well as different particle morphologies. These factors were influenced by the inlet temperature of the spray-drying process. High inlet temperatures led to a positive influence on dryness and particle morphology and therefore on the stability of the sennosides. CONCLUSIONS: Variation of the process conditions affected the resulting particle properties and their storage stability of Sennae fructus extract.

Coatings of Eudragit® RL and L-55 Blends: Investigations on the Drug Release Mechanism.

In a previous study, generally lower drug release rates from RL:L55 blend coated pellets in neutral/basic release media than in acidic release media were reported. The aim of this study was to obtain information on the drug release mechanism of solid dosage forms coated with blends of Eudragit® RL (RL) and Eudragit® L-55 (L55). Swelling experiments with free films were analyzed spectroscopically and gravimetrically to identify the physicochemical cause for this release behavior. With Raman spectroscopy, the swelling of copolymer films could be monitored. IR spectroscopic investigations on RL:L55 blends immersed in media at pH 6.8 confirmed the formation of interpolyelectrolyte complexes (IPECs) that were not detectable after swelling in hydrochloric acid pH 1.2. Further investigations revealed that these IPECs decreased the extent of ion exchange between the quaternary ammonium groups of RL and the swelling media. This is presumably the reason for the previously reported decreased drug permeability of RL:L55 coatings in neutral/basic media as ion exchange is the determining factor in drug release from RL coated dosage forms. Gravimetric erosion studies confirmed that L55 was not leached out of the film blends during swelling in phosphate buffer pH 6.8. In contrast to all other investigated films, the 4:1 (RL:L55) blend showed an extensive swelling within 24 h at pH 6.8 which explains the reported sigmoidal release behavior of 4:1 blend coated pellets. These results help to understand the release behavior of RL:L55 blend coated solid dosage forms.

Rapid Assessment of Tablet Film Coating Quality by Multispectral UV Imaging.

Chemical imaging techniques are beneficial for control of tablet coating layer quality as they provide spectral and spatial information and allow characterization of various types of coating defects. The purpose of this study was to assess the applicability of multispectral UV imaging for assessment of the coating layer quality of tablets. UV images were used to detect, characterize, and localize coating layer defects such as chipped parts, inhomogeneities, and cracks, as well as to evaluate the coating surface texture. Acetylsalicylic acid tablets were prepared on a rotary tablet press and coated with a polyvinyl alcohol-polyethylene glycol graft copolymer using a pan coater. It was demonstrated that the coating intactness can be assessed accurately and fast by UV imaging. The different types of coating defects could be differentiated and localized based on multivariate image analysis and Soft Independent Modeling by Class Analogy applied to the UV images. Tablets with inhomogeneous texture of the coating could be identified and distinguished from those with a homogeneous surface texture. Consequently, UV imaging was shown to be well-suited for monitoring of the tablet coating layer quality. UV imaging is a promising technique for fast quality control of the tablet coating because of the high data acquisition speed and its nondestructive analytical nature.

Multivariate Quantification of the Solid State Phase Composition of Co-Amorphous Naproxen-Indomethacin.

To benefit from the optimized dissolution properties of active pharmaceutical ingredients in their amorphous forms, co-amorphisation as a viable tool to stabilize these amorphous phases is of both academic and industrial interest. Reports dealing with the physical stability and recrystallization behavior of co-amorphous systems are however limited to qualitative evaluations based on the corresponding X-ray powder diffractograms. Therefore, the objective of the study was to develop a quantification model based on X-ray powder diffractometry (XRPD), followed by a multivariate partial least squares regression approach that enables the simultaneous determination of up to four solid state fractions: crystalline naproxen, γ-indomethacin, α-indomethacin as well as co-amorphous naproxen-indomethacin. For this purpose, a calibration set that covers the whole range of possible combinations of the four components was prepared and analyzed by XRPD. In order to test the model performances, leave-one-out cross validation was performed and revealed root mean square errors of validation between 3.11% and 3.45% for the crystalline molar fractions and 5.57% for the co-amorphous molar fraction. In summary, even four solid state phases, involving one co-amorphous phase, can be quantified with this XRPD data-based approach.

How suitable is the measurement of take-off forces for detection of sticking during direct compression of various ibuprofen tablet formulations?

Sticking of tablet formulations to punch surfaces is one of the most common problems observed during tablet manufacture. An inline method proposed for detection of sticking during compression is the measurement of take-off forces, which occur when tablets are detached from the lower punch surface. It has been postulated that the tablet take-off force is a direct indicator of the sticking tendency of a tablet formulation. In the present study, the take-off forces measured during direct compression of sticking ibuprofen tablet formulations were evaluated and compared to the sticking extent of these tablets quantified by HPLC analysis of ibuprofen. As expected, sticking to the lower punch was increased with an increase of the ibuprofen content in the investigated tablet formulations. However, data obtained from take-off force measurements did not correlate with the quantified amount of sticking. Although pronounced sticking was observed, the measured tablet take-off forces remained low even at high drug contents. These results indicate that the tablet take-off force is not a direct indicator of the sticking tendency of ibuprofen tablet formulations. It is suggested that the evaluation of take-off force data requires a differentiated approach. A new interpretation of take-off force data is presented in this paper.

Co-amorphous systems consisting of indomethacin and the chiral co-former tryptophan: Solid-state properties and molecular mobilities.

In this study the influence of an enantiomeric co-former and the preparation method on the solid-state properties and physical stability of co-amorphous systems were investigated. Co-amorphous systems consisting of indomethacin (IND) and chiral tryptophan (TRP) as co-former in its two enantiomeric forms, as racemate, and as conglomerate (equimolar mixture of D- and L-TRP) were prepared. Co-amorphization was achieved by ball milling (BM) and spray drying (SD). The effects of chirality and preparation method on the solid-state properties and physical stabilities of the systems were investigated by XRPD, FTIR and mDSC. Differences in the BM process were caused by the enantiomeric properties of the co-former: The IND/TRP conglomerate (IND/TRPc) turned co-amorphous after 60 min. In contrast, co-amorphization of IND/L-TRP and IND/D-TRP required 80 min of ball milling, respectively, and the co-amorphous IND/TRP racemate (IND/TRPr) was obtained only after 90 min of ball milling. Although the intermolecular interactions of the co-amorphous systems prepared by BM and SD were similar (determined by FTIR), the Tg values differed (∼87 °C for the ball milled and âˆ¼62 °C for the spray dried systems). The physical stabilities of the ball milled co-amorphous systems varied between 3 and 11 months if stored at elevated temperature and dry conditions, with the highest stability for the IND/TRPc system and the lowest stability for the IND/TRPr system, and these differences correlated with the calculated relaxation times. In contrast, all spray dried systems were stable only for 1 month and their relaxation times were similar. It could be shown that the chirality of a co-former and the preparation method influence the solid-state properties, thermal properties and physical stability of IND/TRP systems.

(Co-)amorphization of enantiomers - Investigation of the amorphization process, the physical stability and the dissolution behavior.

A novel approach for improvement of the aqueous solubility of poorly water soluble compounds applying co-amorphous systems was investigated by application of the enantiomers of the chiral amino acid tryptophan (TRP) as the model system. (Co-)amorphization of various forms of crystalline TRP was achieved by ball milling. Solid state analysis demonstrated significant differences in the amorphization tendency and physical stability between the two TRP enantiomers alone, the TRP racemate and an equimolar physical mixture of D- and L-TRP (TRP conglomerate). Ball milling for 6 h was required to obtain fully amorphous plain D- and L-TRP, whereas the TRP racemate and the TRP conglomerate were transformed into their amorphous forms already within 90 and 60 min of ball milling, respectively. Physical stability of the co-amorphous TRP conglomerate was observed for up to 60 d at ambient conditions as well as 40 °C/0 % RH. In contrast, the amorphous TRP racemate showed a reduced physical stability under ambient conditions. Interestingly, the intrinsic dissolution rates of the amorphous TRP conglomerate and racemate were not higher than those of the respective crystalline forms. In conclusion, applying two enantiomers of a chiral compound may be a promising approach for fast amorphization of an API and for improving the physical stability of the resulting amorphous form.

A Novel Two-Chamber Setup for Containment Investigations with Special Focus on the Dustiness of Pharmaceutical Powders Depending on the Airflow.

In the present study, it was shown that a newly developed two-chamber setup (TCS) for containment investigations consisting of an emission and a detection chamber may serve to predict the dustiness of HPAPIs in a sealed system at different flow conditions. These flow conditions include the plain diffusive transport and the diffusive transport with the oppositely directed convective flow of airborne particles of the safe surrogate substance acetaminophen (ACAM). A linear correlation was found between an atomized amount of up to 400 mg of ACAM and the resulting dust emissions. The dust emission was reduced significantly by an oppositely directed convective flow. The results from the examinations, using either atomized ACAM or smoke for the determination of the evacuation time of the detection chamber, indicated that both methods are comparable. Furthermore, computational fluid dynamics (CFD) simulations were performed to determine the evacuation time. A time period of 9 min was sufficient for a reproducible evacuation and a reliable detection of most airborne ACAM particles within the detection chamber. CFD simulations were also carried out to simulate the air velocity resulting from various pressure differences and to visualize the flow of the airborne particles within the detection chamber.

Investigation of drug release from pellets coated with different shellac types.

CONTEXT: Even though most commercially available shellac types meet the specifications of the pharmacopoeias, their physicochemical properties and thus drug release may vary considerably. So far a comparison of drug release from dosage forms coated with different shellac types has not been made. OBJECTIVE: Drug release from pellets coated with different shellac types was investigated and the data correlated to the physicochemical properties of shellac. METHODS: Theophylline pellets were coated with three different commercially available shellac types of Indian and Thai origin. The minimum coating level (CL) to achieve gastric resistance was determined for each shellac type. The drug release characteristics from the different formulations were correlated with the physicochemical properties of the shellac types such as pK(a), acid value, and intrinsic dissolution rate. RESULTS: Gastric resistance was achieved at comparatively low CLs for all investigated shellac types. At pH 7.4 all investigated formulations showed complete drug release within 45 minutes. Drug release at pH 6.8 was prolonged and occurred by swelling and drug diffusion through the coating layer. However, the required minimum CL and drug release profiles especially at pH 6.8 varied considerably. Of the investigated shellac types, the Thai shellac stands out providing both gastric resistance at low CLs and fast drug release at high pH 6.8. CONCLUSION: Although a prediction of the release characteristic could not be made from the pK(a), the intrinsic dissolution rate turned out to be a good indicator for the drug release behavior.

Suitability of various excipients as carrier and coating materials for liquisolid compacts.

CONTEXT: The liquisolid technology is a promising technique for the release enhancement of poorly soluble drugs. With this approach, liquids such as solutions or suspensions of poorly soluble drugs in a non-volatile liquid vehicle are transformed into acceptably flowing and compressible powders. As fast-release liquisolid compacts require a high amount of liquid vehicle, more effective tableting excipients for liquid adsorption are needed to reduce tablet weight. OBJECTIVE: The aim of this study was to investigate the suitability of various novel tableting excipients as carrier and coating materials for liquisolid compacts. MATERIALS AND METHODS: Liquisolid compacts containing the liquid drug tocopherol acetate (TA) as model drug and various excipients were prepared. The effect of liquid drug content on the flowability and tabletability of the liquisolid powder blends as well as the disintegration of the liquisolid compacts was studied. From this data, the maximum liquid adsorption capacity of the respective mixtures of carrier and coating materials could be determined. RESULTS AND DISCUSSION: The liquid adsorption capacity depends on the specific surface area of the investigated excipients. Fujicalin(®) and especially Neusilin(®) are more effective carrier materials for liquid adsorption than Avicel(®), which is often used for liquisolid systems. Moreover, Florite(®) and Neusilin(®) turned out to be more suitable as coating materials than the commonly used Aerosil(®) due to their better tableting properties. CONCLUSION: If Neusilin(®) is used as carrier and coating material instead of Avicel(®) (carrier material) and Aerosil(®) (coating material), the TA adsorption capacity is increased by a factor of 7.

Application of Aquasolv Lignin in ibuprofen-loaded pharmaceutical formulations obtained via direct compression and wet granulation.

AS (Aquasolv) Lignin produced via Liquid Hot Water Pretreatment and Enzymatic Hydrolysis has shown potential as an active pharmaceutical ingredient and/or excipient in solid dosage forms. Moreover, lignin is safe to consume and presents antioxidant and antidiabetic capacity, properties that can add to solid dosage forms in pharmaceuticals. This work aimed to evaluate the performance of tablets produced via direct compression and wet granulation when lignin is used in combination with commercial excipients. In order to find optimal tablet performance, different lignin formulations were assessed, and the concentrations were given by extreme vertices mixture design (13 formulations). The blends were composed of AS Lignin, Microcrystalline Cellulose, and Lactose monohydrate and the optimized blend was found to be 14.53 w/w% of disintegrant, 26.57 w/w% of binder and 58.9 w/w% of AS lignin. This proportion was further used to evaluate the performance of lignin-based tablets in drug release, using Ibuprofen as a drug model (50 w/w% and 70 w/w%) and for comparison of direct compression with wet granulation. Direct compressed tablets resulted in higher drug dissolution rates when compared with wet granulation, nevertheless; both tableting techniques showed promising results for lignin. More than 5 formulations tested in this work are compliant with International Pharmacopoeia regulations for solid dosage pharmaceutical forms, thus AS Lignin shows potential to be used as an excipient in pharmaceutical formulations. INDUSTRIAL RELEVANCE: Industrially, AS Lignin appears as promising excipient in the pharmaceutical technologies as well as boost in the biorefining technologies in the following years. Lignin produced is free of sulfur, can be labelled as clean and environmentally-friendly and in this study, was proven this non-cytotoxic AS lignin can be used for excipients and drug carriers. The findings in this paper showed the use of product formulation for life science purposes, thus stressing one of possibilities for lignin valorization in biorefineries.

Effect of Pullulan as Additive to the Synthetic Polymeric Coating Blend Eudragit® NM-L55 on the Properties of the Resulting Films.

The aim of the present study was to investigate the effect of pullulan as additive to Eudragit® NM-L55 blend film for modification of the resulting film properties with regard to future drug release studies. Films of the plain polymers as well as of those of their blends at different ratios were prepared by an aqueous casting method. Infrared, mechanical, thermogravimetric, water vapor permeance and swelling index studies were performed with blend films of Eudragit® NM-L55 and pullulan. It was demonstrated that intermolecular interactions between Eudragit® NM-L55 and pullulan did not exist. An increasing fraction of up to 30% pullulan in the Eudragit® NM-L55 blend film led to films with rising tensile strength, increasing Young's modulus, and decreasing elongation at break. With increasing fraction of pullulan in the blend films, the thermal stability thereof decreased up to around 400°C. Because of the high hydrophilicity of pullulan, the water vapor permeance increased with increasing fraction of pullulan in the blend films. The addition of pullulan influenced the swelling behavior of the blend films at pH 1.2 and 6.8. The higher the fraction of pullulan in the blend films the earlier the films eroded. These results demonstrate that the polysaccharide pullulan had a major impact on the Eudragit® NM-L55 blend film. It turned out that a fraction of up to 20% pullulan in the synthetic blend film is appropriate to be applied as a coating material. Thus, suitable film properties may be obtained by adjusting the fraction of pullulan in the Eudragit® NM-L55 blend film.

A novel approach to avoid capping and/or lamination by application of external lower punch vibration.

Capping as well as lamination are two common problems, which affect the resulting product quality of the tablet. Usually, capping and lamination occur during or after tablet manufacturing, and may therefore influence follow-up processes such as the coating. In this context, there is an urgent need for approaches to overcome the occurrences of capping and lamination. In the present study, a novel lower punch vibration technique was used to decrease the capping or lamination tendency of different powder formulations. Different microcrystalline cellulose types, as well as an API (acetaminophen), were selected as model powders. The powders were investigated regarding their powder flow, density, particle morphology, and surface area. Moreover, the manufactured tablets were characterized regarding their tablet weight, tensile strength, and capping or lamination indices. It was shown that the capping or lamination tendency was strongly affected by the physical powder properties, the formulation composition, and the adjusted turret speed. In addition, the application of externally applied lower punch vibration led to a pronounced decrease of the capping or lamination tendency and improved mechanical stability of the manufactured tablets.

Citric acid as a pH-modifying additive in an extended release pellet formulation containing a weakly basic drug.

BACKGROUND: An extended release pellet formulation (ACES(R)) of the weakly basic drug propiverine was developed with spheronized citric acid crystals as starter cores. METHOD: Coated pellets, consisting of several layers of functional coatings, were manufactured by fluid bed coating. Different coating levels were examined with regard to their effect on drug release. Release profiles from the formulations with or without pH modifier and the free base as well as the hydrochloride salt of the active ingredient were compared. RESULTS: The coated citric acid starter cores led to a controlled release of the drug and the pH modifier, resulting from modulation of the microenvironmental pH throughout the dissolution period of 17 hours. If microcrystalline cellulose pellets are used as starter cores drug release is strongly pH-dependent. Significant differences in the drug release profiles were observed between the formulations containing the free drug base and those with the hydrochloride salt as a result of an altered microenvironmental pH. CONCLUSION: The presented extended release pellet formulation is able to maintain a low pH within the pellet core and thus a sufficiently high drug solubility. By maintaining a low pH inside the pellets, a controlled drug release can be achieved.