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Controlled and sustained release dosage forms are the focus of worldwide research. These dosage forms facilitate patient compliance by simplifying the dosage regimen, and decrease the risk of adverse effects by reducing large fluctuations in the plasma concentration of the drug. The objective of this study was to formulate a repeat-action tablet to provide a sustained release dose of pseudoephedrine sulfate (PSS), and an immediate release dose of both PSS and loratadine. The release profile was compared to that of a commercially available preparation, Clarityne-D®. This formulation developed presents a novel mechanism of sustaining the release of PSS. The prototype tablet consisted of a sustained release core coated with an ethylcellulose dispersion to introduce a lag phase into the release profile and a second outer film coat incorporating PSS and loratadine. The core comprised an ethylcellulose granulation of PSS compressed into a hydroxypropyl methylcellulose matrix. The release of PSS from prototypes was assessed using USP Apparatus 3, as this apparatus was more representative of in vivo conditions and discriminated more effectively between the different tablet compositions produced during development. All dissolution samples were analysed for PSS and loratadine using validated highperformance liquid chromatographic methods. The prototype sustained release cores were found to be more resistant than the reference product to elevated temperature and humidity (40°C/87% RH) with fewer observed changes to the release profiles following storage for up to six months. This study was a feasibility study to obtain proof of concept. The release profile obtained from the prototype tablets was similar (f₂ = 50.0) to that of the reference product. Further development and optimisation of this dosage form is necessary, including evaluation of the choice of hydrophobic polymer, the effect of compression force and tablet geometry and characterisation of the release mechanism from the coated matrix. Assessment of these factors is necessary in order to optimise the formulation with respect to the desired therapeutic objectives.

This dissertation is comprised of four distinct formulation sections, which are described below: A novel solid dosage formulation was investigated for achieving zero-order drug release profile by combining tablet shape design and tablet membrane film coating. Verapmail (model drug) was compressed into hydrophilic matrix tablet cores of flat-faced and bi-convex shape, which were encapsulated with membrane controlling film. The hydrophilic tablet core contained hydroxypropyl methylcellulose (HPMC) 15 LV, pectin, and Avecil��. The membrane film coating solution was comprised of deionized water, Opadry��, Surelease�� and talc. The combination of membrane film coating and tablet shape design was found to influence in vitro verapamil release profile towards the zero-order release demonstrated by the commercial Covera HS�� (Pharmacia). An alternative formulation for the commercial Bactroban�� (Smithkline Beacham) ointment 2% was developed. Both the texture and consistency of the new ointment were comparable to the Bactroban�� ointment. The new and the commercial formulations were found to be equivalent in drug release by the Bauer-Kirby test. Mupirocin remained unstable in the new formulation. Mg����� was added to help stabilize mupirocin and was shown to complex with mupirocin by nuclear magnetic resonance (NMR). The modified formulation including Mg����� however failed to stabilize mupirocin. The stability assay results showed an average of 67.2% mupirocin recovery along with 25.2% degradation products. A generic omeprazole formulation was developed, which was comprised of nonpareil core, omeprazole matrix layer, and an enteric locating layer of ammoniated hydroxypropyl methylcellulose phthalate (HPMCP) 55S. The new formulation was gastro-resistant in protecting against omeprazole degradation for up to 2 h, but failed to dissolve as rapidly as the commercial Prilosec�� (Astra Merk) in simulated intestinal fluid. The addition of expotab�� to the enteric coating layer failed to improve omeprazole dissolution rate. A novel hot-melt coating methodology utilizing direct blending technique has been developed. The processing steps for the direct blending hot-melt coating are: (a) Hot-melt system preparation; (b) Dispersion/dissolution of the active ingredient(s) in the hot-melt system; (c) Pre-heating of the coating substrate; and (d) Cooling and congealing of the hot-melt on substrate surface. Immunogenic effect was observed in mice administered with enteric-coated ragweed pollen extract (RPE) alpha fraction by the hot-melt coating encapsulation with direct blending method. The effect was not shown to be statistically significant. / Graduation date: 2003

The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H.P.M.C.) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The δ-form, the commercially available stable form and the α and β metastable forms (nomenclature after Muller, 1978) were isolated. The α form was found to be unstable on storage. A 2 fold increase in intrinsic dissolution rate was observed for the metastable β-polymorph compared with the stable δ-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H.P.M.C. and poloxamer 188, were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H.P.M.C. was found to form a "high energy" complex with phenylbutazone which melted 10°C lower than the parent drug. When prepared by spray drying H.P.M.C. inhibited the formation of the metastable β-polymorph of phenylbutazone. A 2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex with phenylbutazone and unlike H.P.M.C. did not inhibit the formation of the β-polymorph. For both crystallised and spray dried samples a 3 fold increase in dissolution rate was obtained at polymer levels of 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of selected phenylbutazone:polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compaction of phenylbutazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (δ-form), samples of spray dried phenylbutazone (β-form) and samples containing different concentrations of H.P.M.C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H.P.M.C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H.P.M.C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H.P.M.C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples.

The physicochemical properties of a drug affect to a large extent its subsequent biological absorption and bioavailability profile. Considerable pharmaceutical interest is therefore directed torwards the improvement of drug dissolution characteristics of drugs with low aqueous solubility. This thesis has considered the controlled modification of drug dissolution profiles by means of incorporating low concentrations of hydrophilic polymers by different processes into a host drug substance. In order to examine this approach and its potential use, the physicochemical, solid state, stability and tableting properties of a poorly aqueous soluble drug, phenylbutazone, in alternative polymorphic form and containing low levels of two hydrophilic polymers - hydroxypropyl methylcellulose (H. P. M. C. ) and the surfactant poloxamer 188 - prepared by both conventional crystallisation and spray drying are reported. As an integral nart of the work attempts were mado to identify the different polymorphic forms of phenylbutazone. The 6-form, the cammerdiallý 4- available stable ýorm and the a and s metastable forr. s (nomenclature after Huller, 1978).. were isolated. The a form was found to be unstable on storage. A .7 fold increase in intrinsic dissolution rate was observed for the metastable s-polymorph compared with the stable 6-polymorphic form. The effect of crystallisation rate on the formation of polymorphs of phenylbutazone was studied using a mini-spray dryer, and slower rates of crystallisation were found to favour polymorph formation. The hydrophilic polymers, H. P. M. C. and poloxamer 188 were incorporated by conventional crystallisation and spray drying into the drug crystal. Samples were subjected to a series of tests including differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and intrinsic dissolution and solubility. When prepared by conventional crystallisation H. P. M. C. was f8und to form a "high energy" complex with phenylbutazone which melted 10 C lower than the parent drug. When prepared by spray drying H. P. M. C. inhibited the formation of the metastable a-polymorph of phenylbutazone. A2 fold increase in intrinsic dissolution rate was observed for crystallised and spray dried samples containing 2% w/w or more added polymer. Poloxamer 188 did not form a complex witý phenylbutazone and unlike H. P. M. C. did not inhibit thejgr gation of the a-polymorph. For both crystallised and spray fo0ld increase in dissolution rate was obtained at polymer levels oý 1% w/w or above. The increase in dissolution has been attributed to facilitated wetting by lowering of interfacial tension rather than through the formation of micelles. The stability of-selected phenylbutazone: polymer samples was tested at elevated temperatures. The stability was found to be affected both by the method of sample preparation and the type of additive. Large breakdowns occurring by a hydrolytic effect were identified for the crystallised phenylbutazone samples containing poloxamer 188. The effects on compact. ion of phenylbu. tazone in alternative form and presence of polymeric additives were studied by compressing samples of similar particle sizes of phenylbutazone as supplied (67form), samples of spray dried phenylbutazone (a-form) and samples containing different concentrations of H. P. M. C. prepared both by conventional crystallisation and spray drying. Compaction data were analysed according to the Heckel relationship and by force transmission ratio as well as from the tensile strengths of prepared tablets. The presence of H. P. M. C. up to 5% w/w concentration in phenylbutazone did not change the mean yield pressure for the crystallised or spray dried samples, although a difference in mean value was observed between the crystallised and spray dried materials, 93.22 MPa and 147.02 MPa respectively. Force transmission was found to be improved for samples containing H. P. M. C. prepared by both techniques and in general, the tablet tensile strengths for crystallised samples containing H. P. M. C. were approximately three times greater than for spray dried samples at equivalent tablet porosity. Differences are attributed to variation in solid state and particulate properties between samples. / Saudi Arabian Government

<p>Robust process monitoring in real-time is a challenge for Continuous Pharmaceutical Manufacturing. Sensors and models have been developed to help to make process monitoring more robust, but they still need to be integrated in real-time to produce reliable estimates of the true state of the process. Dealing with random and gross errors in the process measurements in a systematic way is a potential solution. In this work, we present such a systematic framework, which for a given sensor network and measurement uncertainties will predict the most likely state of the process. As a result, real-time process decisions, whether for process control, exceptional events management or process optimization can be based on the most reliable estimate of the process state.</p><p><br></p><p></p><p>Data reconciliation (DR) and gross error detection (GED) have been developed to accomplish robust process monitoring. DR and GED mitigate the effects of random measurement errors and non-random sensor malfunctions. This methodology has been used for decades in other industries (i.e., Oil and Gas), but it has yet to be applied to the Pharmaceutical Industry. Steady-state data reconciliation (SSDR) is the simplest forms of DR but offers the benefits of short computational times. However, it requires the sensor network to be redundant (i.e., the number of measurements has to be greater than the degrees of freedom).</p><p><br></p><p>In this dissertation, the SSDR framework is defined and implemented it in two different continuous tableting lines: direct compression and dry granulation. The results for two pilot plant scales via continuous direct compression tableting line are reported in this work. The two pilot plants had different equipment and sensor configurations. The results for the dry granulation continuous tableting line studies were also reported on a pilot-plant scale in an end-to-end operation. New measurements for the dry granulation continuous tableting line are also proposed in this work.</p><p><br></p><p></p><p>A comparison is made for the model-based DR approach (SSDR-M) and the purely data-driven approach (SSDR-D) based on the use of principal component constructions. If the process is linear or mildly nonlinear, SSDR-M and SSDR-D give comparable results for the variables estimation and GED. The reconciled measurement values generate using SSDR-M satisfy the model equations and can be used together with the model to estimate unmeasured variables. However, in the presence of nonlinearities, the SSDR-M and SSDR-D will differ. SSDR successfully estimates the real state of the process in the presence of gross errors, as long as steady-state is maintained and the redundancy requirement is met. Gross errors are also detected whether using SSDR-M or SSDR-D. </p><p><br></p>

Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.

Tablets are the most common forms of drug administration. They are convenient to administer and easy to manufacture. However, problems associated with the adhesion of the powders to the tableting tools are common. This phenomenon is known as sticking and even though it has been well documented and studied, it remains poorly understood. The many factors that contribute to good performance of the powders make the sticking problem difficult to solve. The goal of this study is to establish a relationship between the properties measured at the nanoscale to the overall tablet mechanical properties, tablet performance and powder pre-processing induced modifications. By using atomic force microscopy (AFM) we aim to develop an analytical method to characterize the mechanical and adhesive properties of the pharmaceutical powders at the nanoscale. Other methodologies such as scanning electron microscopy (SEM), thermal analyses (DSC, TGA) and tablet strength test were also used. The materials used in this study are commonly used excipients, a sticky drug and magnesium stearate (MgSt). Two different approaches offered by AFM were employed: sharp tip imaging and colloidal probe force measurements. Nano-mechanical properties of the materials were evaluated with a sharp tip cantilever showing that higher adhesion correlates with higher tablet cohesion and that both are significantly affected by the presence of MgSt. AFM characterization of the particle surface mechanical properties at the nanoscale was also used to detect the crystallinity and amorphicity levels of the materials. New approaches to presenting such data considering the particle heterogeneity and to track the dynamics of surface recrystallization are revealed. Adhesive interactions between a steel sphere and sticky and non-sticky powders were performed with the colloidal probe technique. Sticky materials presented a higher adhesion against the steel surface, and reveal the mechanism of stickiness. This work thus contributes to the provision of predictability of the performance of formulations at an early stage of the development process. / <p>QC 20170315</p>

No / The pharmaceutical powder and tableting process is simulated using a combined finite-discrete element method and contact dynamics for irregular-shaped particles. The particle-scale formulation and two-stage contact detection algorithm which has been developed for the proposed method enhances the overall calculation efficiency for particle interaction characteristics. The irregular particle shapes and random sizes are represented as a pseudo-particle assembly having a scaled up geometry but based on the variations of real powder particles. Our simulations show that particle size, shapes and material properties have a significant influence on the behaviour of compaction and deformation.