Pharmaceutical Blends Research Articles

Using a Mass Balance to Determine the Potency Loss during the Production of a Pharmaceutical Blend

The manufacture of a blend containing the active pharmaceutical ingredient (API) and inert excipients is a precursor for the production of most pharmaceutical capsules and tablets. However, if there is a net water gain or preferential loss of API during production, the potency of the final drug product may be less than the target value. We use a mass balance to predict the mean potency loss during the production of a blend via wet granulation and fluidized bed drying. The result is an explicit analytical equation for the change in blend potency a function of net water gain, solids losses (both regular and high-potency), and the fraction of excipients added extragranularly. This model predicts that each 1% gain in moisture content (as determined by a loss on drying test) will decrease the API concentration of the final blend at least 1% LC. The effect of pre-blend solid losses increases with their degree of superpotency. This work supports Quality by Design by providing a rational method to set the process design space to minimize blend potency losses. When an overage is necessary, the model can help justify it by providing a quantitative, first-principles understanding of the sources of potency loss. The analysis is applicable to other manufacturing processes where the primary sources of potency loss are net water gain and/or mass losses.

Study of the effects of feed frames on powder blend properties during the filling of tablet press dies

This paper studies systematically the effect of a feed frames, a device used in rotary tablet presses to drive the powders into compression dies, on the properties of the powders entering the tablet press dies. The work focused on the effect of blend composition, feed frame parameters (blade speed, residence time), and rotary die disc parameters (die disc speed, die diameter) on the flow pattern, uniformity of die filling, applied shear, and the flow properties of pharmaceutical blends. The flow pattern suggests a stratified filling of the dies and therefore, non-uniform properties of the tablets. The amount of powder entering the dies depended on blend flow properties, feed frame speed, and dies disc speed. In addition, blend properties changed significantly as the powder flowed through the feed frame. The flowability of lubricated blends improved significantly as the number of feed frame blade passes increased, decreasing in turn the RSD of the die filling weight.

Flowability characterisation of drug–excipient blends using a novel powder avalanching method

The scope of the work is twofold, first to introduce a new avalanche testing instrument and secondly to characterise flowability of pharmaceutical blends comprising of coarse and fine particles. The results were compared with established powder characterisation instruments like the angular shear cell and a flow through orifice tester. These different methods were applied to a broad concentration range of binary mixtures comprising coarse, well-flowing lactose and micronised, poorly flowing albendazole. Some of the mixtures were further analysed with scanning electron microscopy. The results showed clear changes in the flow behaviour of the mixtures that were considered as critical flow concentrations (CFCs). At least three drug concentrations were observed for which the flow behaviour essentially changed. Accordingly, different flow regions were identified, which were explained on the basis of changed particle packing configurations. A theoretical model successfully provided a first estimation of the initial two CFCs. In conclusion, the novel avalanche testing instrument provided complementary information to conventional flowability methodologies, and a thorough assessment of pharmaceutical blends is needed to avoid CFCs in view of a robust formulation development and hence with respect to building quality into the design of the solid dosage forms.

Effects of shear and electrical properties on flow characteristics of pharmaceutical blends

AbstractThis article examines the effects and interactions of shear rate, shear strain on electrical and flow properties of pharmaceutical blends. An unexpectedly strong relation between the flow and passive electrical properties of powders is observed to depend on the shear history of the powder bed. Charge density, impedance, dielectrophoresis, flow index, and dilation were measured for several pharmaceutical blends after they were subjected to a controlled shear environment. It was found that the increase in the shear strain intensified the electrical properties for blends that did not contain MgSt. The opposite effect was found in blends lubricated with MgSt. Different shear conditions resulted in different correlations between flow index and dilation. Flow properties of powders were found to improve with continuous exposure to shear strain. It was also found that flow properties correlated to charge acquisition and impedance for different shear treatments. © 2009 American Institute of Chemical Engineers AIChE J, 2010

Effects of Electrostatic Charging on Pharmaceutical Powder Blending Homogeneity

During the pharmaceutical powder blending process, electrostatic charges generate and accumulate unavoidably due to particle-particle and particle-wall collision. The effect of electrostatic charging on pharmaceutical powder blending homogeneity was investigated on two binary blending systems: (1) lactose as an excipient with caffeine as an Active Pharmaceutical Ingredient (API) and (2) Micro-crystalline Cellulose (MCC) with caffeine. Three different blending procedures were conducted: (1) conventional blending without any charge control, (2) blending with simultaneous charge neutralization, and (3) blending combined with a corona charging process. It was found that the average API concentration variation increases with the increase of charge-to-mass ratio of final blend samples. In other words, the presence of uncontrolled electrostatic charges has an adverse effect on powder blend uniformity. Elimination or minimization of electrostatic charges also appears to have a negative impact on powder blend uniformity. In contrast, blending of positively charged excipient material and negatively charged API material leads to a better blend uniformity. The controlled electrostatic charging opens an opportunity for improving uniformity of the pharmaceutical blending process.

An observed correlation between flow and electrical properties of pharmaceutical blends

We study the relation between flow and electrical conductivity of multiple formulations of pharmaceutical powder blends. Ten formulations were tested, consisting of two excipient sets, two active preparations, and a variety of food-grade additives including magnesium stearate (MgSt), and ionic and conductive materials such as ascorbic acid, talc, sodium carbonate, colloidal silica and TiO 2. Electrical impedance, flow index and dilation were independently measured for all of the blends, and a strong correlation was found between every pair of these three properties. The relation between flow and dilation has been observed before; we find for the first time that there is an exponential relationship between flow index or dilation and impedance. This indicates that cohesive powder behavior depends on powder electrical properties, raising the questions of whether additives such as MgSt affect friction and conductivity per se and what mechanism and phenomenon links cohesion and conductivity.

Mechanoradical-Induced Degradation in a Pharmaceutical Blend during High-Shear Processing

Mechanically generated radicals were shown to affect short-term stability of a model pharmaceutical formulation during high-shear processing. A formulation containing an oxidatively sensitive drug, either amorphous or crystalline, and a polymeric excipient was high-shear mixed and the resulting short-term degradation was determined with HPLC. High-shear mixing of the excipients was also carried out before drug addition to isolate effects on excipients versus those directly on the drug. Short-term drug stability was found to be strongly dependent on the amount of shear added to excipients prior to drug addition, regardless of morphology. A mechanism for the observed degradation based on mechanically generated radicals from microcrystalline cellulose is proposed. These results indicate that excipient high-shear exposure needs to be considered in regards to drug stability.

Assessment of Segregation Potential of Powder Blends

Pharmaceutical blends consist of several components each with its own unique characteristics, with different size, shape, density, and particle-particle interactions. With so many degrees of complexity, prediction of segregation behavior becomes intractable. The objective of this study was to develop a segregation test method or a segregation tool that would assess the segregation potential of blends. Literature reports generally seek to predict the segregation behavior based on only one mechanism by which the segregation occurs, primarily sifting or fluidization. This study makes an attempt to combine both of these mechanisms by which segregation occurs. A test is developed and used to assess the segregation behavior of blends at large scale and compare the content uniformity results of tablets with the results of the segregation test. The segregation testing model was successful in predicting the segregation tendency of the formulation and also in rank ordering large scale formulation blends based on their segregation potential. A segregation risk classification system is proposed to assess the potential of segregation at large scale.

Cohesive, multicomponent, dense powder flow characterization by NIR

Non-aerated powder flows are frequently encountered in downstream pharmaceutical processes. Such flows occur at the entrance of powder compression units, and their characteristics are of great interest because any powder agglomeration or segregation can be detrimental to the quality of the final solid oral dosage form. This work was aimed at developing a process analytical technology (PAT) method, based on near-infrared spectroscopy (NIR) for the in-line powder flow characterization of pharmaceutical formulations. An Ibuprofen drug formulation was selected for study. A bench-scale hopper system was assembled to monitor powder flow behaviour. An in-line commercial NIR Axsun spectrometer and probe were chosen to collect in-line spectral data on dense, multicomponent, non-aerated powder flow prior to compression. Spectra were collected on flowing mannitol and pharmaceutical product blends. A specially designed, non-contact sampling interface allowed the collection of representative process powder flow spectra without affecting blend uniformity. A partial least squares chemometric model was developed for laboratory-prepared samples, to quantitatively determine the flowing powder's active pharmaceutical ingredient (API) level. Static sample spectra and flowing pure mannitol spectra proved to have a high degree of reproducibility. The model's standard error of calibration was 2.95% of the API level with a R 2 of 0.991. Flowing blend powder spectra and API estimates showed variations consistent with those seen in model samples. The average values for flowing pharmaceutical blends were close to the API concentration, indicating that the proposed procedure was statistically acceptable. The model is considered very promising, and some improvements would lead to its final acceptance at production scale as a PAT tool.

Influence of shear intensity and total shear on properties of blends and tablets of lactose and cellulose lubricated with magnesium stearate

A new technique to quantify the effects of shear intensity and total shear on the homogeneity, flowability and bulk density of a lubricated free-flowing pharmaceutical blend and on properties of resulting tablets is presented. A modified Couette cylindrical cell with uniformly spaced pins is used to create a uniform shear environment. The range of lubricant concentrations explored is 0–2% (on a mass basis). Sheared blends are used to produce tablets in the Presster™ (a simulator of an actual tablet press), allowing us to correlate the shear history of the blend (shear intensity and total shear) with the crushing hardness of tablets. The results show that the larger the total shear, the more homogeneous the blend. Bulk density increases with total shear until reaching a distinctive plateau. Results also indicate that high total shear affects the blend flow properties. For tablets, crushing hardness decreases as concentration of lubricant and total shear increase. Interestingly, and unexpectedly, under constant total shear, shear intensity affects the crushing hardness of tablets only slightly.

Determination of active ingredient within pharmaceutical preparations using flow injection mass spectrometry

Two separate pharmaceutical blends, one containing 2% caffeine by weight, the other containing 2% creatine by weight, and 200 mg caffeine tablets were examined in this study. The purpose of the analyses was to determine the feasibility of using flow injection mass spectrometry for the quantitative analysis of active ingredient within a drug product or other form of pharmaceutical preparation. For more precise and accurate measurements, it was necessary to incorporate an internal reference within the samples. Further, flow injection analysis showed to provide quicker, more facile method development than the application of chromatographic separation. Samples were analyzed over an analyte concentration range of 5.0–15.0 μg/mL. Analyte selectivity was obtained through the observance of the ( M + H) + ions generated by positive electrospray ionization of each of the analytes ( m/ z 195 for caffeine and m/ z 132 for creatine), and accurate quantitation was achieved by determining the ratio of the analyte response versus the response of the incorporated reference compound. Sample-to-sample precision in these measurements was less than 3%, recovery values were shown to be accurate to within ±3% of the actual values, and both analytical methods proved to be linear over the assay range ( R 2 ≥ 0.999). Due to the excellent selectivity and low detection limits available to mass spectrometric detection, flow injection mass spectrometric analysis could be particularly applicable for analysis of formulations that contain either low doses of active ingredient, active ingredient with low solubility, or active ingredient that does not possess a strong chromophore. Additionally, this type of methodology shows to be conducive for rapid method development.

A Homogeneity Study Using NIR Spectroscopy: Tracking Magnesium Stearate in Bohle Bin-Blender

A method was developed for studying mixing of cohesive pharmaceutical mixtures. A combination of accurate sampling and NIR spectroscopic analysis was developed as a suitable method to determine homogenization of magnesium stearate as a function of blending variables. A typical pharmaceutical blend containing a ratio 35:64:1 lactose, avicel, and magnesium stearate was used as a model system. The method accounted for variability of the concentration of magnesium stearate as well as variability of the excipients. Levels of magnesium stearate as low as 0.05% could be resolved by the method, and showed a predicting confidence interval above 98%.

Modeling crystallization processes: transformation diagrams

The crystallization processes, cold crystallization and solidification from the melt, are analyzed using a modified isoconversional method to obtain the transformation diagrams: temperature-heating/cooling rate and temperature–time. The thermal study is performed by means of differential scanning calorimetry. All transformation curves are obtained from non-isothermal calorimetric experiments. The usefulness of the method is illustrated by analysis of the crystallization process in three model materials: a Fe–Ni based material, two pharmaceutical blends with PEG and a PP-PE copolymer with different additives. Good agreement is observed between the transformation curves obtained by calculation and the experimental data, which verifies the reliability of the method.

NIR Method Development for Monitoring of Pharmaceutical Powder Blending

NIR Method Development for Monitoring of Pharmaceutical Powder Blending

The Use of Particle Characteristics to Elucidate Mix Homogeneity in Binary Powder Blends

A series of binary powder blends comprising microcrystalline cellulose (Avicel® PH101), α-lactose monohydrate, or anhydrous theophylline were prepared in order to investigate the ability of particle-characteristics measurements to express the homogeneity of the resulting mixture. It is postulated that fundamental physical characteristics, such as particle-specific surface area, true density, and size distribution, can be used to quantitatively ascertain mix homogeneity in routine pharmaceutical blending operations.

On-Line Monitoring of Powder Blend Homogeneity by Near-Infrared Spectroscopy

Near-infrared spectroscopy is evaluated as an on-line technique for monitoring the homogeneity of a pharmaceutical blend during the blending process. Blends containing 10% sodium benzoate (model active), which provided an aromatic functionality typical of many pharmaceutical compounds, 39% microcrystalline cellulose (Avicel PH102), 50% lactose, and 1% magnesium stearate were developed to mimic the properties of an actual pharmaceutical blend. A twin-shell V-blender was modified to allow installation of a diffuse reflectance fiber-optic probe at the axis of rotation, and spectra were collected during three experiments using a commercially available near-infrared spectrophotometer. In each experiment, blender control and spectral data collection were controlled by a compilation of software packages. The experiments detected spectral changes which eventually converged to a point of constant variance. Further analysis of the spectral data showed the blend is homogeneous long before a typical blending period is complete. Near-infrared spectroscopy has proven to be a feasible and effective method for the "real time" noninvasive determination of homogeneity in a pharmaceutical blend.