Automated Non-Sterile Pharmacy Compounding: A Multi-Site Study in European Hospital and Community Pharmacies with Pediatric Immediate Release Propranolol Hydrochloride Tablets.

Pharmacy compounding, the art and science of preparing customized medications to meet individual patient needs, is on the verge of transformation. Traditional methods of compounding often involve manual and time-consuming processes, presenting challenges in terms of consistency, dosage accuracy, quality control, contamination, and scalability. However, the emergence of cutting-edge technologies has paved a way for a new era for pharmacy compounding, promising to redefine the way medications are prepared and delivered as pharmacy-tailored personalized medicines. In this multi-site study, more than 30 hospitals and community pharmacies from eight countries in Europe utilized a novel automated dosing approach inspired by 3D printing for the compounding of non-sterile propranolol hydrochloride tablets. CuraBlend® excipient base, a GMP-manufactured excipient base (pharma-ink) intended for automated compounding applications, was used. A standardized study protocol to test the automated dosing of tablets with variable weights was performed in all participating pharmacies in four different iterative phases. Integrated quality control was performed with an in-process scale and NIR spectroscopy supported by HPLC content uniformity measurements. In total, 6088 propranolol tablets were produced at different locations during this study. It was shown that the dosing accuracy of the process increased from about 90% to 100% from Phase 1 to Phase 4 by making improvements to the formulation and the hardware solutions. The results indicate that through this automated and quality controlled compounding approach, extemporaneous pharmacy manufacturing can take a giant leap forward towards automation and digital manufacture of dosage forms in hospital pharmacies and compounding pharmacies.

Rapid particle size measurement using 3D surface imaging.

The present study introduces a new three-dimensional (3D) surface image analysis technique in which white light illumination from different incident angles is used to create 3D surfaces with a photometric approach. The three-dimensional features of the surface images created are then used in the characterization of particle size distributions of granules. This surface image analysis method is compared to sieve analysis and a particle sizing method based on spatial filtering technique with nearly 30 granule batches. The aim is also to evaluate the technique in flowability screening of granular materials. Overall, the new 3D imaging approach allows a rapid analysis of large amounts of sample and gives valuable visual information on the granule surfaces in terms of surface roughness and particle shape.

Effect of fluidisation activity on end-point detection of a fluid bed drying process.

The influence of inlet air humidity variations on fluid bed drying end-point detection was the primary focus here. Various drying end-point criteria based on temperature and humidity measurements were compared. Seasonally changing inlet air humidity affects the moisture content of the finished granules, as long as the drying process remains unchanged. However, a specific moisture content of the finished granules is commonly desired after fluid bed drying. When experimental batches of varying inlet air humidity were compared at the beginning of the drying phase, the temperature of the granules increased linearly as the humidity of the inlet air increased. This effect causes variation in moisture contents of the final granules of different batches when the fixed temperature of the mass is used as an end-point criterion. With varying inlet air humidity, the often used DeltaT temperature difference method resulted in more precise estimation of the drying end-point than the constant temperature criterion. In this study new insights were found into the correlation between moisture content and temperature of the fluidising mass. Fluidisation activity greatly affected detection of drying end-point. Use of the DeltaT criterion requires proper fluidisation throughout the process.

Novel description of a design space for fluidised bed granulation.

The physical measurements of a fluid bed granulator can be exploited in construction of an operating window, a design space, for process performance. The purpose of this study was to determine the influence of inlet air humidity changes on temperature in different parts of a granulator system, on fluidisation behaviour and on the particle size of the final granules. A humidifying setup was constructed on a bench-scale fluid bed granulator that enabled elevated humidity levels and sharp humidity changes of the inlet air. Ibuprofen granules were produced at the various inlet air humidity levels classified as low, intermediate and high. A novel fluidisation parameter was developed. The more improperly the particles were fluidising the smaller was the relationship of airflow rate and fan speed. Four different failure modes were identified and classified, based on the fluidisation parameter: over-fluidisation, risk of improper fluidisation, improper fluidisation and collapsed bed. It was possible to construct process trajectories for smooth fluidisation, which the optimal granulation process should follow.

A novel set of behavioural indicators for measuring perception of food by cats.

Behavioural indicators provide a promising approach for objective assessment of the perceptions of animals. In cats, the frequency of specific behaviours as indicators of perception has been studied in connection with food palatability. The aim of this study was to expand that knowledge by identifying behavioural indicators correlating with three degrees of palatability. Thirty-four pet cats were presented with three types of items: favoured food (FF), favoured food with a placebo mini-tablet hidden inside (TFF) and non-favoured food (NFF). The items were presented in a pseudo-randomised sequence, with six trials per item and 18 trials per cat. The behaviour of cats before, during and after eating, or refusing to eat, was video-recorded. Two trained observers, blinded to the types of food items, independently determined the frequency of 16 behavioural patterns on the video recordings. The data were analysed using a mixed logistic regression model. Five behavioural patterns differentiated FF from NFF; 'flick ears backwards', 'lick nose, not eaten', 'flick tail' and 'groom body' were more frequent with NFF, whereas 'lick lips' was more frequent with FF. One indicator, 'drop item', was more frequent with TFF than FF. These findings provide evidence of new behavioural indicators for objective assessment of food perception in cats. The findings also have practical applicability in designing a novel palatability test to be utilised in developing veterinary pharmaceuticals with improved palatability for cats.

Role of water in the physical stability of solid dosage formulations.

The interaction of moisture with pharmaceutical solids is highly crucial to an understanding of water-based processes, for example, manufacturing processes or prediction of solid dosage form stability and shelf life. Both the active pharmaceutical ingredient (API) and excipients in the formulation have different moisture sorption properties that can result in unexpected processing-induced phase transitions and they can affect solid-state phase transitions in the final dosage forms. The character of excipient effects on the stability of formulation. Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The aim of the present study was to investigate the water sorption properties of different excipients, model the sorption isotherms, examine the phase transitions, and identify differences of excipients in solid dosage form stability using dynamic vapor sorption analysis, near-infrared spectroscopy, and X-ray diffraction methods. The thermal processing was carried out with a variable temperature X-ray powder diffractometer to compare the dehydration behavior of wet excipients and evaluate solid-state properties during heating. These results showed that despite some limitations, moisture sorption isotherms of excipients are useful in predicting solid-state stability, interactions at early stages of formulation development, and effects of moisture on physicochemical properties of the final dosage forms.

Characterization of polymorphic solid-state changes using variable temperature X-ray powder diffraction.

The aim of this study was to use variable temperature X-ray powder diffraction (VT-XRPD) to understand the solid-state changes in the pharmaceutical materials during heating. The model compounds studied were sulfathiazole, theophylline and nitrofurantoin. This study showed that the polymorph form of sulfathiazole SUTHAZ01 was very stable and SUTHAZ02 changed as a function of temperature to SUTHAZ01. Theophylline monohydrate changed via its metastable form to its anhydrous form during heating and nitrofurantoin monohydrate changed via amorphous form to its anhydrous form during heating. The crystallinity of SUTHAZ01, SUTHAZ02 and theophylline monohydrate were very high and stable. Nitrofurantoin monohydrate was also very crystalline at room temperature but during heating at lower temperatures the crystallinity decreased and started to increase strongly at the temperature where the sample had changed to the anhydrous form. The average crystallite size of sulfathiazole samples varied only a little during heating. The average crystallite size of both theophylline and nitrofurantoin monohydrate decreased during heating. However, the average crystallite size of nitrofurantoin monohydrate returned back to starting size at higher temperatures. These analyses showed that VT-XRPD can be used to effectively characterize polymorphic changes during heating.

Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation.

Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potential (amorphous low-substituted hydroxypropylcellulose, modified maize starch, partially amorphous silicified microcrystalline cellulose, and crystalline alpha-lactose monohydrate) were granulated with varying amounts of purified water. Off-line evaluation of wet masses containing nitrofurantoin anhydrate and excipient (1:1) was performed using an X-ray powder diffractometer (XRPD) and near-infrared spectroscopy, and drying phase was evaluated by variable temperature XRPD. Only amorphous excipient in the formulation retarded hydrate formation of an active pharmaceutical ingredient (API) at high water contents. Hygroscopic partially crystalline excipient hindered hydrate formation of API at low water contents. Crystalline excipient was unable to control hydrate formation of API. The character of excipient affects the stability of formulation. Thus, correct selection of excipients for the formulation can control processing-induced phase transitions and improve the storage stability of the final dosage form.

Physical stability and moisture sorption of aqueous chitosan-amylose starch films plasticized with polyols.

The short-term stability and the water sorption of films prepared from binary mixtures of chitosan and native amylose maize starch (Hylon VII) were evaluated using free films. The aqueous polymer solutions of the free films contained 2% (w/w) film formers, glycerol, or erythritol as a plasticizer, as well as acetic acid (1%) and purified water. Characterization of the present fresh and conditioned film formers and free films was done using X-ray diffraction analysis, determination of moisture sorption isotherms, and near infrared spectroscopy. The results indicated that clear changes in the crystallinity of the films are evident within a 3-month period of storage, and the changes in the solid state are dependent on the plasticizer and storage conditions. When stored at ambient conditions for 3 months, the aqueous chitosan-amylose starch films plasticized with erythritol exhibited a partly crystalline structure. This was as a result of sugar recrystallisation due to the high hydrogen bonding. The respective films plasticized with glycerol and stored at 25 degrees C/60% relative humidity (RH) or at 40 degrees C/75% RH remained flexible and amorphous for at least 3 months. The water sorption of the free films greatly increased as a function of storage time at 75 and 95% RH. The second derivative spectra of starting material and free films were capable of distinguishing the internal water from the free water after storage at different relative humidities. Free water resulted in a separate band at a lower wavelength (1903 nm) in comparison to the structured absorbed water band at 1920 nm, in the case of films the free water resulted in a band around 1900 nm.

Effects of excipients on hydrate formation in wet masses containing theophylline.

Transformations between solid phases in dosage forms can lead to instability in drug release. Thus, it is important to understand mechanisms and kinetics of phase transformations and factors that may influence them. During wet granulation theophylline shows pseudopolymorphic changes that may alter its dissolution rate. The aim of this study was to investigate whether excipients, such as alpha-lactose monohydrate or the highly water absorbing silicified microcrystalline cellulose (SMCC) can influence the hydrate formation of theophylline. In particular, the aim was to study if SMCC offers protection against the formation of theophylline monohydrate relative to alpha-lactose monohydrate in wet masses after an overnight equilibration and the stability of final granules during controlled storage. In addition, the aim was to study the use of spectroscopic methods to identify hydrate formation in the formulations containing excipients. Off-line evaluation of materials was performed using X-ray powder diffractometry, near infrared and Raman spectroscopy. alpha-Lactose monohydrate with minimal water absorbing potential was not able to prevent but enhanced hydrate formation of theophylline. Even though SMCC is able to take large amounts of water into its internal structure, it was able to inhibit the formation of theophylline monohydrate only at low moisture contents, not at the amounts of water needed to form granules. Both the spectroscopic methods used could identify the hydrate formation even though there were excipients in the formulation.

Role of excipients in hydrate formation kinetics of theophylline in wet masses studied by near-infrared spectroscopy.

Hydrate formation is a phase transition, which can occur during wet granulation. This kind of processing-induced transformation (PIT) can influence the quality of a finished product. The aim of the study was to investigate the effect of excipients on the kinetics of hydrate formation in wet masses. Anhydrous theophylline was chosen as the hydrate-forming model drug compound and two excipients, silicified microcrystalline cellulose (SMCC) and alpha-lactose monohydrate, with different water absorbing properties, were used in formulation. An early stage of wet massing was studied with anhydrous theophylline and its 1:1 (w/w) mixtures with alpha-lactose monohydrate and SMCC with 0.1g/g of purified water. The changes in the state of water were monitored using near-infrared spectroscopy, and the conversion of the crystal structure was verified using X-ray powder diffraction (XRPD). SMCC decreased the hydrate formation rate by absorbing water, but did not inhibit it. The results suggest that alpha-lactose monohydrate slightly increased the hydrate formation rate in comparison with a mass comprising only anhydrous theophylline.

Comparison of the effects of two drying methods on polymorphism of theophylline.

Processing-induced transformations in drug formulation may induce adverse biopharmaceutical changes in the finished product. During the drying phase of wet granulation, theophylline monohydrate transforms either the stable (form I), or a polymorphic, metastable (form I(*)) form of anhydrous theophylline. We investigated the effect of two drying methods (multichamber microscale fluid bed dryer MMFD) or variable temperature X-ray powder diffractometer (VT-XRPD) on the relative amounts of the different theophylline forms remaining in the dried granules. Granules were analyzed using XRPD and near-infrared spectroscopy. Form I(*) was the predominant form of theophylline after drying at 40-50 degrees C with both drying techniques. Although drying at temperatures over 50 degrees C produced mostly form I, more than 20% of form I(*) remained even at 90 degrees C when drying in MMFD. In these conditions, humidity had little influence on the amount of form I(*) in the granules. In contrast, drying in a VT-XRPD at 60 degrees C produced form I already during the first 15min. Using additional drying methods, including MMFD, during the preformulation stage can be more informative about the possible polymorphic transformations and their underlying mechanisms, such as triboelectrification or recrystallization, in drug ingredients during the manufacturing process.

Evaluating optimal combination of clodronate and bioactive glass for dental application.

Both clodronate and bioactive glass are mostly used alone as treatment in various bone diseases but, they are also known to have beneficial effects in dental application. The same processes that lead to loss of bone can also result in alveolar bone loss. The object of this study was to define the optimal combination of clodronate and bioactive glass (BAG) to be used locally in dentistry. The evaluation was based on measurements and solid state properties obtained with pH, scanning electron microscopy (SEM), differential scanning calorimetric (DSC), X-ray powder diffraction (XRPD), Fourier transform infrared spectroscopy (FTIR) and Focused-ion beam (FIB) and energy dispersive X-ray spectroscopic (EDS) mapping. The results indicate that if too much calcium clodronate precipitation is formed, the activity of BAG is affected negatively. As there is more reaction surface to form calcium clodronate, similar to the amount of clodronate present, this reduces the bioactivity of BAG. Therefore, in dental treatment the most suitable BAG and clodronate combination product would have apatite (HA, hydroxyapatite) formation ability and amount of clodronate enough to enhance the bioactivity of BAG allowing HA formation. Based on combinations investigated, the one with 200mg clodronate and 1 g BAG with particle size 0.5-0.8 mm was chosen to be the most promising for local dental application.

Interaction of bioactive glass with clodronate.

Bone tissue engineering is a rapidly growing area of research involving the use of bioactive glass (BG) alone and in combination with different materials. The objective of this study was to investigate the interaction of BG with clodronate. Characterisation of the interaction between BG and clodronate was undertaken using; scanning electron microscopy (SEM), X-ray powder diffraction (XRPD), Fourier transform Raman spectroscopy and Fourier transform infrared spectroscopy (FTIR). The interaction was examined in vitro with respect to the ion exchange and surface modification on the surface of the bioactive glass in the combination product. The results showed clear ion exchange enhancement by clodronate. Additionally, this ion exchange was more extensive and long lasting in the combination product than in BG alone. Clodronate promotes the activity of the BG and a calcium clodronate precipitation is formed. It can be assumed that this solid combination could be used in clinical applications. Therefore, it can be concluded that clodronate makes a beneficial environment for BG and could enhance also the apatite formation of BG.

Granule size control and targeting in pulsed spray fluid bed granulation.

The primary aim of the study was to investigate the effects of pulsed liquid feed on granule size. The secondary aim was to increase knowledge of this technique in granule size targeting. Pulsed liquid feed refers to the pump changing between on- and off-positions in sequences, called duty cycles. One duty cycle consists of one on- and off-period. The study was performed with a laboratory-scale top-spray fluid bed granulator with duty cycle length and atomization pressure as studied variables. The liquid feed rate, amount and inlet air temperature were constant. The granules were small, indicating that the powder has only undergone ordered mixing, nucleation and early growth. The effect of atomizing pressure on granule size depends on inlet air relative humidity, with premature binder evaporation as a reason. The duty cycle length was of critical importance to the end product attributes, by defining the extent of intermittent drying and rewetting. By varying only the duty cycle length, it was possible to control granule nucleation and growth, with a wider granule size target range in increased relative humidity. The present study confirms that pulsed liquid feed in fluid bed granulation is a useful tool in end product particle size targeting.