• The application of porous adsorbents to increase the dissolution rate of low solubility drugs

      Pan, Xiaohong; Augsburger, Larry L. (2002)
      The purpose of this research was to further the understanding of the crystalline to amorphous phase transitions that occur when some crystalline drugs are physically mixed with porous adsorbents. This phenomenon may provide a convenient means of enhancing the bioavailability of some poorly soluble drugs that exhibit dissolution-rate limited absorption. Indomethacin (IMC), a high permeability and low solubility drug, was used as a model drug. Three different grades of silica gel (SG) having different pore sizes and surface areas were used as the porous adsorbent. DSC and XRPD analysis showed that the loss in IMC crystallinity, or amorphization of IMC occurs rapidly during the mixing process and was found to occur within 5 minutes. Amorphization was also found to be independent of mixing intensity and time under the experimental conditions studied. The extent of amorphization is dependent upon the IMC/SG ratio, the particle size of IMC and SG and the amount of moisture in SG. The extent of amorphization in the mixtures increased as the ratio of IMC to SG decreased and as the IMC particle size decreased. The extent of amorphization was not highly dependent on the SG surface area or pore size since the bulk of the SG surface area is contained within the pore structure, and is only partially available to crystalline IMC. Blocking the H-bonding silanol groups on SG by chemical modification significantly reduced the extent of amorphization of crystalline IMC. This indicated that the amorphization of crystalline IMC in mixtures with SG occurs as a result of H-bonding between IMC and the silanol groups on the surface of SG. IMC/SG mixtures showed improved dissolution compared to pure crystalline IMC. The improvement in dissolution was directly related to the amount of amorphous IMC in the mixture. IMC/SG mixtures stored at room temperature and under desiccation are physically and chemically stable up to 4 months. To maintain the physical/chemical stability and improved dissolution performance, IMC/SG mixtures should be stored protected from heat, humidity and light. This work has demonstrated the potential of using SG as a means to induce amorphization of crystalline, sparingly soluble drugs such as IMC and to improve in-vitro dissolution.
    • A comparative study of the formulation requirements of dosator and dosing disc encapsulators, simulation of plug formation, and creation of rules for an expert system for formulation design

      Heda, Pavan Kumar; Augsburger, Larry L. (1998)
      Objectives. The objectives of this study were: (i){A0}to develop a 'semi-quantitative' definition of fluidity, lubricity and compactibility requirements for the two most commonly used types of automatic capsule filling machines - the dosator and the dosing disc type, (ii) to simulate powder plug formation and explore the low force powder compression physics of the process, (iii) to utilize artificial neural networks (ANNs) as a pattern recognition tool to forecast (a) the encapsulation performance of an automatic capsule filling machine, and (b) the impact of formulation characteristics and filling principle on product performance, and (iv) to develop new or modified decision trees for an expert system for formulation design. Methods. Laboratory research - Model formulations were developed differing either in their degree of fluidity, lubricity, or compactibility. Carr's index, ejection force, and plug strength were used for gauging the fluidity, lubricity and compactibility respectively. The model formulations were encapsulated on Hofliger-Karg (H&K) GKF- 400 and Zanasi LZ-64 encapsulators instrumented for monitoring compression and ejection forces. The formulations were evaluated for percent coefficient of fill-weight variation, ejection force, plug strength, and dissolution of model drugs, hydrochlorothiazide and ascorbic acid. A programmable tablet compaction simulator especially tooled for plug compression was used. Plugs of different heights at different punch speeds were made using a saw-tooth waveform. Non-laboratory research - A group of experts from the industry were consulted to provide a pool of expertise for identifying new and improved rules for an expert system for formulation support. A survey of the practices of formulators and industry policies concerning the development of formulations for hard gelatin capsules was conducted with a panel of experts. A literature search was also conducted to identify information on excipients specific to capsule formulation. Results and conclusions. From the laboratory research on the instrumented automatic capsule filling machines it was observed that there were differences in the formulation requirements of the dosator type machine, such as, the Zanasi LZ-64 Vs the dosing disc type machine, such as, the Hofliger Karg (H&K) GKF-400. The results show that an optimal degree of fluidity is required in a formulation for successful encapsulation on either type of filling machine. A relatively lower level of lubricant may be sufficient for encapsulation on the H&K machine as compared to the Zanasi. A higher degree of cohesiveness is needed for clean processing on the Zanasi machine as compared to the H&K. The study provided a range of formulation characteristics that would be suitable for transferring formulations between these machines. Optimal points for all the input and response variables for successful encapsulation on either type of machine were obtained using ANNs. Using the programmable tablet compaction simulator to simulate plug formation tablet compaction models such as, Heckel analysis, Shaxby-Evans's exponential relationship, Kawakita's pressure-volume relationship, and coefficient of lubrication 'R' were successfully applied to the plug formation process. It was concluded that as compressibility is required of powder formulations on automatic capsule filling machines, these tableting models could be used to characterize the physico-mechanical properties of formulations required for efficient plug formation. This research has provided a better understanding of the interplay of formulation and machine operating variables and formulation design strategies that, when incorporated into an expert system, will facilitate the determination of rational, robust formulations for capsules. The database generated in this study will be incorporated in an expert system in the form of both 'domain specific rules' and cautionary 'flags'.
    • The development of a radiotelemetric data acquisition system to measure punch force and displacement on a high-speed rotary tablet press and an investigation of the rate-sensitive behavior of pharmaceutical materials

      Muller, Francis Xavier; Augsburger, Larry L. (1993)
      The first phase of this project was the design, construction, and implementation of a system to acquire punch force and displacement data from a high speed rotary tablet. The system was unobtrusive and allowed for the manufacture of tablets under normal production conditions, in batches, with a feedframe. The instrumentation was shown to be accurate, sensitive, reliable, and robust. The data was collected via a radiotelemetry link. This system allowed for the full characterization of the compaction process on a high-speed rotary tablet press. A number of parameters were shown to deviate significantly from the theoretical values, including: punch displacement, total punch speed, and contact time. Also, the relationship between the area under the force-time curve and the net work of compaction was shown to be essentially non-linear and material dependent. Increased tableting rate caused a decrease in tablet tensile strength for plastically deforming materials. A number of compaction parameters were studied to explain the changes in tablet hardness that included: net work, power, and elastic recovery. No parameter alone appeared to explain the changes in tensile strength. A study performed on a compaction simulator illustrated that the loss of hardness as a result of increased rate of output was caused by the effects of a number of parameters. It was concluded that one parameter can't be used to explain rate-sensitive tensile strength behavior. Force-displacement and Heckel behavior was shown to be confounded by the total punch speed of the compression event. It was concluded that the area under the force-displacement curve did not relate well to tablet tensile strength at different rates of output and Heckel Analysis should be performed using "saw-toothed" displacement-time waveforms. Two methods to decrease the loss of tensile strength as a result of increased rate of output were studied. The use of precompression was shown to deliver a compression event which supplied greater net work and greater tensile strength with a slight increase in punch speed when compared to main compression at the same contact time. Activation of the overload spring was shown to increase the net work and tensile strength when compared to a normal compression event. It was concluded that both methods appear to make harder tablets for some formulations as a result of compaction dynamics and not due to increased contact time.
    • The development of an extended-release metoprolol tartrate dosage form, its in vitro and in vivo evaluation and the applications of in vitro-in vivo correlation across release mechanisms as a predictor of in vivo performance

      Mahayni, Houda; Augsburger, Larry L. (1997)
      In the past four years three guidances have been prepared for the pharmaceutical industry which dealt with different aspects of extended-release dosage forms. This dissertation focused on one main issue from each of the three guidances. The first issue addressed pharmaceutical equivalence requirements. The second issue examined how multiple changes in formulation and process variables affect in vitro dissolution test result. The third issue concentrated on in vitro-in vivo correlation (IVIVC) as a predictor of in vivo performance across release mechanisms. A metoprolol tartrate extended-release capsule formulation was developed using fluid bed multiprocessor equipment with Wurster insert. Sugar spheres were drug-layered with metoprolol tartrate, seal-coated with Opadry (hydroxypropyl methylcellulose) and film-coated with Surelease (ethylcellulose). This dosage form was compared to a reference metoprolol tartrate matrix tablet dosage form which was formulated using Methocel K100LV (hydrodroxypropyl methylcellulose) as a hydrophilic polymer to retard the release. The mechanisms of release between both dosage forms differ. In the case of the tablet (reference) product, release is a function of the square root of time and the release rate can be controlled by the tablet porosity, addition of soluble solids, and the ratio of drug to carrier. The mechanism and kinetics of drug delivery from the capsule (test) formulation depend on the nature of the film and can be controlled by film porosity and thickness. For insoluble membranes made of ethylcellulose, drug release depends primarily on diffusion and partitioning of the drug into the membrane. Dissolution tests using different media, agitation speeds and methods were performed on both formulations to determine how the differences in dosage forms in terms of appearance or type (multiparticulate vs single unit) and release mechanism affect in vitro release. An in vitro-in vivo correlation (IVIVC) between plasma concentration and dissolution rate for matrix tablet formulation of the same drug was used to predict the in vivo performance of the capsule formulation. A clinical study was conducted using the capsule formulation and the bioavailability parameters derived from this study were compared to those predicted from the matrix tablet IVIVC. Both formulations released drug similarily under different dissolution testing conditions (f2>75). While the extent of release from both formulations was similar in vivo, the rate of release was not. This finding was also reflected in the predictions made using the matrix tablet IVIVC. The area under the curve (AUC) was adequately predicted (error<3%) whereas, the maximum concentration (Cmax) which is a bioavailability parameter that reflects rate in addition to extent of absorption was not well predicted(error>20%). The results demonstrate: (1) the f2 criteria used to determine in vitro profile similarity between formulations may not be suitable when the dosage forms being compared differ in release mechanisms, and/or (2) the IVIVC is formulation and mechanism dependent. The differences found in the in vivo absorption rates of these two formulations reflect differences in the dynamics of stomach emptying and intestinal transport between a multiparticulate dosage form compared to a monolithic matrix tablet dosage form.
    • Effect of sorbed water on the efficiency of super disintegrants: Physical and mechanistic considerations

      Hahm, Huijeong Ashley; Augsburger, Larry L. (2002)
      Optimizing the use of the super disintegrants (SD) requires a better understanding of their mechanism of action than currently exists. Because their functionality is fundamentally related to the ability to draw liquid into tablet matrices, it was hypothesized that higher initial moisture contents from sorbed water would decrease their ability to effect rapid disintegration. In testing this hypothesis, a device that automatically measures disintegration time was designed and constructed, sensitive tests to evaluate disintegrant efficiencies were developed, and the mechanisms of action of SDs were studied by relating several physical changes caused by sorbed moisture to their ability to disintegrate tablets. AcDiSolRTM PolyplasdoneRTM XL, and PrimojelRTM, representative of different classes of SDs, were studied. The effect of sorbed water on plasticity, tablet tensile strength, x-ray powder diffraction pattern, and morphology were evaluated. A slowly disintegrating partially soluble tablet matrix was designed based on artificial neural network and statistical experimental design models and employed with the USP disintegration apparatus. With increasing moisture content, all SDs were plasticized and their tablets exhibited lower tensile strength. No change in morphology was apparent for AcDiSolRTM stored at relative humidities up to 75.3% at room temperature, but PrimojelRTM particles agglomerated. Upon compression with sand, AcDiSolRTM and PrimojelRTM particles did not appear to have deformed, but PolyplasdoneRTM XL particles agglomerated. Except for AcDiSolRTM, SDs stored at higher humidity caused slower disintegration of anhydrous lactose tablets. Disintegration times were slower when SDs with higher water content were incorporated in the designed slowly-disintegrating tablet matrix. The automatic disintegration test apparatus was found suitable for evaluating the disintegration of rapidly disintegrating tablets and enabled the determination of whether tablet disintegration was predominantly controlled by diffusion or interfacial separation. This device also enabled the systematic design and evaluation of tablet matrices for fast disintegration in the mouth suitable for oral administration of drugs to patients unable to swallow tablets. SDs exhibited different physical and functional sensitivities to sorbed moisture. In general, AcDiSolRTM was found to be the least sensitive and the most effective disintegrant. The mechanism of tablet disintegration was dependent both on the SD and the nature of the tablet matrix.
    • Elucidation of the nature of the plug formation process and its implications in a dosing disk machine using an instrumented Hofliger Karg GKF 330 capsule filling machine

      Cropp, John Worth; Augsburger, Larry L. (1992)
      Particle deformation, stress transmission, and bonding in compacts have been studied extensively at higher force levels such as those associated with tableting equipment. However, fundamental questions exist regarding the nature of particle behavior during compaction at low forces, such as seen with the dosator and dosing-disk type automatic capsule filling machines. There are published reports in the literature citing unusual dissolution behavior of finished capsule dosage forms for which no explanation is available. An Hofliger Karg GKF 330, a dosing-disk machine, previously instrumented to monitor tamping force, was further modified to allow for simultaneous monitoring of brass ring movement and movement of individual tamping pins. These data were used to determine powder displacement. Powder displacement data were combined with tamping force data to determine work of compaction and perform Heckel analysis. Model formulations, exhibiting classic brittle or plastically deforming type behavior, were evaluated using the instrumented Hofliger Karg GKF 330 by varying overload spring type, pin penetration setting, and number of tamps. Capsule plugs were examined for evidence of particle deformation, plug strength, plug weight, and release of a slightly soluble drug, hydrochlorothiazide. Plugs were evaluated using scanning electron microscopy, BET gas adsorption surface area, and mercury intrusion porosimetry to provide detailed information to the behavior of materials when compacted at low forces. Microcrystalline cellulose based plugs exhibited minimal particle deformation whereas anhydrous lactose based plugs exhibited evidence of fracture. Both formulations exhibited increased plug strength and weight with higher tamping forces which resulted from the use of a larger wire diameter overload spring, increased pin penetration setting, or both. No effect upon the release of hydrochlorothiazide was observed as a result of varying number of tamps or tamping force.
    • Evaluation of a capacitive sensor for wet granulation monitoring in a high shear mixer

      Corvari, Vincent John; Augsburger, Larry L. (1992)
      The objectives of this dissertation are to evaluate and compare a new capacitive sensor, a watt meter and a strain gaged torque sensor for wet granulation monitoring in a high shear mixer. Toward this end, a 10 L vertical high shear mixer was instrumented to monitor power consumption, torque, moisture distribution and capacitive changes during agglomeration. The percent moisture content related linearly to the amplitude channel response. Yield values provided a rheological property to relate with power consumption and torque measurement. In a comparative study of the two most commonly used monitoring techniques, torque measurement was shown to be more sensitive than power consumption measurement, but this increased sensitivity did not offer any advantage over power consumption measurement. In another comparative study the amplitude channel of the capacitive sensor appears to more clearly differentiate between binder levels in hydrous lactose-hydroxypropyl methylcellulose granulations than either power consumption or torque measurement, based on particle size distributions. Four formulations were used to evaluate the effect of varying agitation rate and rate of fluid addition on the granulation endpoint determined by the capacitive sensor. For hydrous lactose (Lactose) with 4% polyvinylpyrrolidone K 29/32 (PVP), dicalcium phosphate anhydrous milled (DCP) with 5% PVP and a one to one mixture of Lactose and microcrystalline cellulose (MCC 102) with 5% PVP, the amplitude channel of the capacitive sensor predicted similar endpoints based on particle size, flow rate and crushing strength-compression force profiles under varying agitation and addition rates. The apparent independence of the amplitude channel to variations in agitation rate and rate of liquid addition suggests that this component of the capacitive sensor may be scaled up. The amplitude channel was successfully scaled up from a 50 L to a 130 L horizontal high shear mixer based on particle size, flow and crushing strength-compression force profiles for Lactose/PVP formulations. In addition, the amplitude channel was able to compensate for differences in moisture distribution when the chopper was employed in the scale-up study. A centrifugation technique, thermogravimetric analysis and nuclear magnetic resonance (NMR) inversion recovery technique were developed to compare the interaction of moisture with each of the filler systems used in the endpoint detection study. (Abstract shortened by UMI.)
    • Evaluation of the functional equivalence of different sources of super disintegrants in pharmaceutical tablets

      Shah, Umang Subodh; Augsburger, Larry L. (1996)
      Disintegrants are substances included in tablet formulations to cause the compressed tablet to break apart and promote drug dissolution when placed in an aqueous environment. In the past two decades, three categories of newer disintegrants have come into widespread use. These substances are chemically modified starch (sodium starch glycolate), chemically modified cellulose (croscarmellose sodium) and a synthetic polymer (crospovidone). Because of their high efficiency at low levels of addition compared to traditional starch, these substances are often called "super disintegrants." One objective of this dissertation was to identify among different sources of disintegrants of each type meeting NF standards, differences in physical properties thought to be related to functionality. A second objective was to develop standard performance tests and use those tests to determine the hypothesized relationship between these physical differences and disintegrant functionality. Dissolution was performed on a model tablet formulation of hydrochlorothiazide using either an insoluble filler (dicalcium phosphate dihydrate) or a soluble filler (spray-dried lactose) and test disintegrants at a 1% level. Disintegrants tested exhibited significant differences in the rate and extent of liquid uptake and in the ability to develop axial and radial disintegrating forces. Lowering the pH altered the rate and extent of liquid uptake of sodium-starch glycolate and croscarmellose sodium. Since there are no ionizable groups in crospovidones, lowering the pH did not affect their liquid uptake performance. Sources of crospovidone containing larger particle size fractions showed greater rate of liquid uptake, however crospovidones with greater porosity showed greater extent of liquid uptake. Liquid uptake study on sieve fractions of crospovidones showed greater rate and extent of uptake for larger sieve cuts, whereas smaller sieve cuts of starch glycolates showed greater rate and extent of liquid uptake. For tablets containing water-insoluble filler dicalcium phosphate, disintegration times for sources of crospovidone containing larger particle size were lower and showed correspondingly faster dissolution rates. The rate of disintegration and dissolution followed the same rank order as the extent of liquid uptake. However, when the filler was changed to spray-dried lactose, although the disintegration of all tablets containing different sources of crospovidone was faster than in the insoluble filler, no significant differences were detected in either the disintegration times or dissolution amongst the disintegrants from different sources. Tablets containing croscarmellose sodium or sodium starch glycolate from different sources, in either filler showed no significant differences in disintegration times and their corresponding rates of dissolution were also not different, indicating that dissolution of hydrochlorothiazide is the rate limiting step. This study indicates that liquid uptake study, particle size and porosity should be included in crospovidone monographs, whereas liquid uptake studies and/or settling volume studies in a low pH medium should be included in compendial monographs for sodium starch glycolate and croscarmellose sodium. (Abstract shortened by UMI.)
    • In silico formulation: Application of artificial intelligence in support of hard gelatin capsule formulation of biopharmaceutics classification system class II drugs

      Wilson, Wendy I.; Augsburger, Larry L. (2004)
      Guo et al have demonstrated that a prototype hybrid expert network (PEN) for capsule formulation is capable of yielding formulations that meet specific manufacturing and performance criteria for the model Biopharmaceutics Classification System (BCS) Class II drug piroxicam (Pharm Tech NA (26:9) 2002, p. 44). Purpose. The overall objective of this project is to assess the application of artificial intelligence in capsule formulation support of BCS Class If drugs. The phases of this project include: (1) Characterize model BCS Class II drugs based on physiochemical properties associated with solubility; (2) Evaluate the dissolution performance of the capsule formulations; (3) Generalize the PEN for formulation of model drugs; (4) Apply a Bayesian Network (BN) to formulation development of the model drugs. Methods. The model drugs used in this project were carbamazepine (CAR), chlorpropamide (CHL), diazepam (DIA), ibuprofen (IBU), ketoprofen (KET), naproxen (NAP) and piroxicam (PIR). The micromeritic properties, aqueous solubilities, contact angles, specific surface areas (SSA) and intrinsic dissolution rates (IDR) of these actives were characterized. Capsule formulations of each active were manufactured based on a Box-Behnken experimental design, varying the filler type/ratio and the amounts of lubricant, wetting agent and disintegrant. Dissolution performance of these capsules was characterized using USP standard dissolution media. This data was used to generalize the PEN and to develop a BN. Results. The model drugs were subdivided into weak acids and weak bases. A dataset containing SSA, contact angles, IDRs and percent drug dissolved at 10, 30 and 45 minutes for the model drugs was used as the basis for training the PEN. The system was successfully able to predict the dissolution performance of the model drugs. A BN was successfully developed to model the relationships between formulation variables and dissolution performance. Conclusions. Testing of the PEN indicates that the system can predict the dissolution performance of BCS Class II drugs and can be successfully generalized. The BN has proven to be a useful tool for formulation development. Within the scope of this research, this project proves that artificial intelligence can be successfully applied to pharmaceutical research and development.
    • The influence of formulation and processing variables on the phytochemical profile of Hypericum perforatum extract

      Kopelman, Susan Hu; Augsburger, Larry L. (2001)
      Objective. St. John's Wort's (SJW) complex composition-activity relationship presents a major challenge in developing dosage forms (df) that exhibit appropriate quality and performance. To attempt to meet this challenge, this research examined: (1) selected physicochemical properties of commercial SJW extracts; (2) how certain excipients and processing parameters may affect the phytochemical profile (PP); (3) the utility of similarity metrics in summarizing PPs, and; (4) formulated SJW capsule df performance. Methods. An adapted analytical method was developed and used to compare PPs of commercial extracts and assess their stability and compatibility. Modifications to conventional isothermal stress testing paradigms were explored. Formulated SJW capsules and tablets were prepared to study any potential effect of compression force on PPs and the stability of formulations filled into gelatin and HPMC capsules. A gelatin capsule formulation was developed and tested for df performance per compendial methods. Results. The adapted analytical method proved suitable for assessing the phytochemicals of interest. Extracts exhibited similar total hypericins contents (marker compounds), but greatly different overall PPs. The extracts were moderately fluid, highly hygroscopic, and exhibited compression properties unlike those of typical fillers. Storage paradigms were suitable for excipient compatibility testing when controls of neat material are employed. Phytochemicals were not uniformly compatible with excipients. Malic acid did not stabilize the PP. Similarity metrics conveniently summarized changes to overall PP profiles. Some components in neat and formulated SJW were adversely influenced by tableting compressive forces. Phytochemicals had varying stability towards capsule shell composition and sealing: neat SJW typically was more sensitive. A capsule formulation of SJW was developed that easily surpassed compendial df performance specifications. Conclusion. This research provides guidance in formulating SJW dfs, and by analogy, other botanical dfs. Similarity metrics are recommended for summarizing the PP of botanicals when activity cannot be adequately represented by one or two marker compounds.
    • Mechanical characterization of ibuprofen, naproxen, and their spherically crystallized products

      Anderson, Stephen R.; Augsburger, Larry L. (1997)
      The objectives of this study were to establish a rational basis for choosing parameters for conducting the tensile strength and indentation hardness test on pharmaceutical compacts, to describe the changes in tableting indices based on the different parameters, to develop a method to spherically crystallize ibuprofen, and to compare the mechanical and micromeritic properties of spherically crystallized ibuprofen and naproxen to the starting materials. This work described the importance of establishing the appropriate test parameters for tensile strength and indentation hardness tests so that reliable and predictive tableting indices could be determined. The fracture strength for diametral compression of ibuprofen compacts was determined for two modes of stress application, constant stress rate and constant strain rate. The tensile strength for diametral compression of ibuprofen and naproxen compacts was determined using a constant strain rate (0.05 to 16 mm/min). The static indentation hardness (Meyer hardness) of ibuprofen and naproxen compacts was determined at varying solid fractions and indentor depth of penetration. Results from these studies were used to establish an appropriate rate of stress application during diametral compression and an appropriate depth of penetration for indentation hardness testing in order to calculate tableting indices. The tableting indices calculated from the aforementioned properties were: the brittle fracture index (BFI), the best case bonding index (BIb), the worst case bonding index (BIw), the brittle/viscoelastic bonding index (bBIv), and the viscoelastic index (VI). In addition, changes in compactibility between the starting materials and their spherically crystallized products were assessed through the analysis of Athy-Heckel profiles. A comparison of micromeritic properties included particle size, porosity, surface area, bulk density, tap density, true density, and flowability as measured by the Carr Index. The spherically crystallized products of ibuprofen and naproxen were shown to be free flowing, less compressible, and more compactible than the starting materials. The spherically crystallized ibuprofen product was optimized for improved tensile strength, bonding index, and minimal particle size using response surface experimental design methodology. Key process factors in the quasi-emulsion solvent diffusion method employed to spherically crystallize ibuprofen were: the amount of additive, hydroxypropylmethyl cellulose, added to the nonsolvent, the agitation rate during the crystallization process, and the amount of agglomerating solvent. Naproxen was spherically crystallized using a solvent change method adopted from the open literature. Thermal analysis and x-ray powder diffraction analysis showed that both ibuprofen and naproxen spherically crystallized products were the same highly crystalline form as the starting materials. The relative contribution of the different micromeritic properties to the changes in the mechanical properties was exemplified by the change in BFI. (Abstract shortened by UMI.)
    • The relationship between finished granule properties and the outputs of granule endpoint monitoring devices and the rheological properties of the wet masses

      Vuppala, Murali Krishna; Augsburger, Larry L. (1998)
      Endpoint monitoring is critical in high shear granulation. The objective of this research was to study the relationship between the outputs of selected granulation endpoint monitoring devices (capacitive sensor, wattmeter and torque transducer) and the finished granule properties, and to study the rheological properties of the wet granules in an attempt to correlate the outputs of granulation monitoring devices with the properties of the forming granules. Two granulation systems were studied in a Littleford high shear mixer: lactose, representing soluble materials and dicalcium phosphate (DCP), representing insoluble materials. Polyvinylpyrrolidone was the binder and water was the binder liquid. A face centered central composite design was used. The amplitude channel of the capacitive sensor monitored resistive properties of the material and the frequency channel monitored capacitive changes. Analysis showed that the capacitive sensor outputs were dependent on the impeller speed, particle size distribution of the granules, the quantity of fines and the moisture content. The effects of these variables on torque and power consumption differed with lactose and DCP granulations. For both granulations, impeller speed had greater effect on the power consumption than any other variable studied. The capacitive sensor was more sensitive in differentiating the particle size of the raw materials than torque or power consumption. An Instron dynamic testing system was used to perform creep analysis on the wet masses. Total compliance and the torque and power consumption values were linearly related. Compliance values increased with impeller speed, moisture content, particle size of the raw material, binder concentration, and were found to be intrinsic to each material. When a mixture MCC and lactose was studied, the rheological properties could be related to the each material in the mixture. The capacitive sensor monitored the material properties directly and could be recommended as the endpoint monitoring device of choice because of its ability to relate its output to the particle size distribution of the finished granules.
    • Structural stability and in vitro biological activity of proteins during microencapsulation into biodegradable polymers

      Nellore, Ranjani Vimala; Augsburger, Larry L.; Bhagat, Hitesh R. (1995)
      The effects of solvent treatments and physical stresses encountered by two proteins, ribonuclease A and adenosine deaminase, during the process of microencapsulation into biodegradable polymeric microspheres were examined. The protein stability at each step of the microencapsulation procedure was monitored by using fluorescence, circular dichroism and sodium dodecyl sulfate-polyacrylamide gel electrophoresis methods to characterize the tertiary structure, secondary structure and aggregation characteristics, respectively. The enzymatic activity of the proteins was determined by spectrophotometric assays. The microencapsulated product was characterized for size distribution, surface morphology, encapsulation efficiency, protein release profiles and protein activity. For both the proteins, solvent treatment did not lead to aggregate formation. For ribonuclease A, heptane treatment caused a change in the environment of the tyrosine residues of the protein which was manifested as an additional peak in the fluorescence emission spectrum. However, the secondary structure remained intact. Adenosine deaminase showed a significant change in the secondary structure following solvent treatment. The fraction of {dollar}\alpha{dollar}-helix and {dollar}\beta{dollar}-sheet showed a decrease with a corresponding increase in random structure. No changes were observed in the fluorescence spectrum. These changes did not affect the enzymatic activity of either protein and it was concluded that the active site of the enzyme which is responsible for substrate binding was not affected by the stresses of microencapsulation. The microspheres had smooth surfaces and a mean diameter of 24 {dollar}\mu{dollar}m. The encapsulation efficiency was high in the case of ribonuclease A but less than 50% for adenosine deaminase. During release studies, a burst release of about 60% of the encapsulated protein was seen in both cases. Complete release of ribonuclease A from the microspheres occurred in a week. Sustained but incomplete release of adenosine deaminase from the microspheres occurred over 25 days. Both proteins showed loss of enzymatic activity in the release samples. Although proteins may be resistant to inactivation due to solvent treatment and physical stresses, interactions with the polymer matrix during release may result in loss of activity and inability to obtain sustained release of active protein.
    • A study of selected physico-mechanical aspects of the extrusion and spheronization processes and their relationship to the design of pelletted pharmaceutical formulations

      Shah, Rajen Dhirubhai; Augsburger, Larry L. (1991)
      Pellets are becoming increasingly popular as unique delivery systems. Of the several processes available to prepare these pellets, extrusion/spheronization is better suited to produce pellets with the desired attributes such as narrow size distribution, high bulk density and low friability. The prevalent empirical approach to optimize this process warrants a complete understanding of its rheological requirements. The specific objectives are to identify and define criteria such as the plastic yield value which may govern the success of this process, and to assess the contribution of Microcrystalline cellulose (MCC) to this process. Toward this end, a twin screw extruder EXDS-60 was specially instrumented to measure screen pressure and screen temperature. In addition, techniques were developed to measure three properties of the wet mass, viz., yield value, tensile strength, and yield loci, in an attempt to relate to the qualities of ideal extrudates for spheronization. Using a model lactose/MCC system, statistically designed experiments were planned to study the relationship between formulation variables, rheological parameters of the wet mass, and quality parameters of the dried pellets. The instrumentation output provided new insights into the interplay between formulation and extrusion process variables and is further expected to assist in the design of formulations by providing objective measures of extrudability. The rheogram of the wet masses provided an important parameter in yield value. The tensile strength measurement with a specially designed split-die system provided valuable information regarding the mechanism of bonding within the wet mass. Also, the combination of yield value and weight of extrudate (as an indirect measure of tensile strength) could be used to predict the shape of the pellets. The yield loci parameters were useful in detecting over-wet granulations. Upon careful analysis of the experimental data, it was apparent that there was a critical range of rheological parameters within which pellets having optimum sphericity and narrow size distribution can be prepared. This critical range was defined as the rheological "window" within which both extrusion and spheronization can be carried out satisfactorily. Initially, MCC is perceived to be an essential "cure-all" ingredient for all extrusion/spheronization problems. Based on a consideration of the physico-chemical properties of MCC, and evidence from scanning electron microscopy, its unique contribution was attributed to its high internal porosity, and the formation of a particle network in the localized areas of the wet mass. In conclusion, the knowledge gained from this investigation facilitates the design of pelletted formulations by reducing reliance on empiricism.