Influence of Formulation and Processing Factors on Stability of Levothyroxine Sodium Pentahydrate

Stability of formulations over shelf-life is critical for having a quality product. Choice of excipients, manufacturing process, storage conditions, and packaging can either mitigate or enhance the degradation of the active pharmaceutical ingredient (API), affecting potency and/or stability. The purpose was to investigate the influence of processing and formulation factors on stability of levothyroxine (API). The API was stored at long-term (25°C/60%RH), accelerated (40°C/75%RH), and low-humidity (25°C/0%RH and 40°C/0%RH) conditions for 28 days. Effect of moisture loss was evaluated by drying it (room temperature, N₂) and placed at 25°C/0%RH and 40°C/0%RH. The API was incubated with various excipients (based on package insert of marketed tablets) in either 1:1, 1:10, or 1:100 ratios with 5% moisture at 60°C. Commonly used ratios for excipients were used. The equilibrium sorption data was collected on the API and excipients. The API was stable in solid state for the study duration under all conditions for both forms (potency between 90% and 110%). Excipients effect on stability varied and crospovidone, povidone, and sodium laurel sulfate (SLS) caused significant API degradation where deiodination and deamination occurred. Moisture sorption values were different across excipients. Crospovidone and povidone were hygroscopic whereas SLS showed deliquescence at high RH. The transient formulation procedures where temperature might go up or humidity might go down would not have major impact on the API stability. Excipients influence stability and if possible, those three should either be avoided or used in minimum quantity which could provide more stable tablet formulations with minimum potency loss throughout its shelf-life.     

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 α-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. Published: October 6, 2005     

Dry Powder Inhalers: Study of the Parameters Influencing Adhesion and Dispersion of Fluticasone Propionate

Interactions between particles are dependent on the physicochemical characteristics of the interacting particles but it is also important to consider the manufacturing process. Blending active pharmaceutical ingredient (API) with carrier is a critical stage that determines the blend homogeneity and is the first step towards obtaining the final quality of the powder blend. The aim of this work was to study parameters that influence the interactions between API and carrier in adhesive mixtures used in DPI and their effect on API dispersion. The study was done with fluticasone propionate blended with lactose ‘Lactohale 200’. The study was based on the influence of the operating conditions (speed, mixing time, resting steps during mixing), the size of the carrier and the storage conditions on the blend properties and on the API dispersion. The quality of the blends was examined by analysing the API content uniformity. Adhesion characteristics were evaluated by submitting mixtures to a sieving action by air depression with the Alpine air-jet sieve. Aerodynamic evaluation of fine particle fraction (FPF) was obtained using a Twin Stage Impinger; the FPF being defined as the mass percentage of API below 6.4 μm. For good dispersion and therefore good homogeneity of the API in the carrier particles, speed and powder blending time have to be sufficient, but not too long to prevent the appearance of static electricity, which is not favourable to homogeneity and stability. The FPF increases with the decrease in the carrier size. The storage conditions have also to be taken into consideration. Higher humidity favours the adhesion of API on the carrier and decreases the FPF.KEY WORDS: adhesion, DPI performance, fluticasone propionate, operating parameters     

Reactive Impurities in Excipients: Profiling,Identification and Mitigation of Drug–Excipient Incompatibility

Reactive impurities in pharmaceutical excipients could cause drug product instability, leading to decreased product performance, loss in potency, and/or formation of potentially toxic degradants. The levels of reactive impurities in excipients may vary between lots and vendors. Screening of excipients for these impurities and a thorough understanding of their potential interaction with drug candidates during early formulation development ensure robust drug product development. In this review paper, excipient impurities are categorized into six major classes, including reducing sugars, aldehydes, peroxides, metals, nitrate/nitrite, and organic acids. The sources of generation, the analytical method for detection, the stability of impurities upon storage and processing, and the potential reactions with drug candidates of these impurities are reviewed. Specific examples of drug–excipient impurity interaction from internal research and literature are provided. Mitigation strategies and corrective measures are also discussed.     

Vascular functioning and the water balance of ripening kiwifruit (Actinidia chinensis) berries

Indirect evidence suggests that water supply to fleshy fruits during the final stages of development occurs through the phloem, with the xylem providing little water, or acting as a pathway for water loss back to the plant. This inference was tested by examining the water balance and vascular functioning of ripening kiwifruit berries (Actinidia chinensis var. chinensis 'Hort16A') exhibiting a pre-harvest 'shrivel' disorder in California, and normal development in New Zealand. Dye labelling and mass balance experiments indicated that the xylem and phloem were both functional and contributed approximately equally to the fruit water supply during this stage of development. The modelled fruit water balance was dominated by transpiration, with net water loss under high vapour pressure deficit (D(a)) conditions in California, but a net gain under cooler New Zealand conditions. Direct measurement of pedicel sap flow under controlled conditions confirmed inward flows in both the phloem and xylem under conditions of both low and high D(a). Phloem flows were required for growth, with gradual recovery after a step increase in D(a). Xylem flows alone were unable to support growth, but did supply transpiration and were responsive to D(a)-induced pressure fluctuations. The results suggest that the shrivel disorder was a consequence of a high fruit transpiration rate, and that the perception of complete loss or reversal of inward xylem flows in ripening fruits should be re-examined.     

Multiblock PLS analysis of an industrial pharmaceutical process

The performance of an industrial pharmaceutical process (production of an active pharmaceutical ingredient by fermentation, API) was modeled by multiblock partial least squares (MBPLS). The most important process stages are inoculum production and API production fermentation. Thirty batches (runs) were produced according to an experimental planning. Rather than merging all these data into a single block of independent variables (as in ordinary PLS), four data blocks were used separately (manipulated and quality variables for each process stage). With the multiblock approach it was possible to calculate weights and scores for each independent block. It was found that the inoculum quality variables were highly correlated with API production for nominal fermentations. For the nonnominal fermentations, the manipulations of the fermentation stage explained the amount of API obtained (especially the pH and biomass concentration). Based on the above process analysis it was possible to select a smaller set of variables with which a new model was built. The amount of variance predicted of the final API concentration (cross-validation) for this model was 82.4%. The advantage of the multiblock model over the standard PLS model is that the contributions of the two main process stages to the API volumetric productivity were determined.     

Slowly developing drought stress increases photosynthetic acclimation of Catharanthus roseus

Our understanding of plant responses to drought has improved over the decades. However, the importance of the rate of drought imposition on the response is still poorly understood. To test the importance of the rate at which drought stress develops, whole-plant photosynthesis (P(net) ), respiration (R(dark) ), daily carbon gain (DCG), daily evapotranspiration (DET) and water use efficiency (WUE) of vinca (Catharanthus roseus), subjected to different drought imposition rates, were investigated. We controlled the rate at which the substrate dried out with an automated irrigation system that allowed pot weight to decrease gradually throughout the drying period. Fast, intermediate and slow drying treatments reached their final pot weight [500 g, substrate water content (θ) ≈ 0.10 m3 m(-3) ] after 3.1, 6.6 and 10 days, respectively. Although all drying treatments decreased P(net) and R(dark) , slow drying reduced P(net) and R(dark) less than fast drying. At a θ < 0.10 m3 m(-3) , DCG and DET in the slow drying treatment were reduced by ≈50%, whereas DCG and DET in the fast drying treatment were reduced by 85 and 70% at a θ of 0.16 m(3) m(-3) . Plants exposed to slow drought imposition maintained a high WUE, even at θ < 0.10 m3 m(-3) . Overall, physiological responses to low θ were less severe in plants subjected to slow drying as compared with fast drying, even though the final θ was lower for plants exposed to slow drying. This suggests that the rate at which drought stress develops has important implications for the level of acclimation that occurs.     

Mass balance analysis of contaminated heparin product

A quantitative analysis of a recalled contaminated lot of heparin sodium injection U.S. Pharmacopeia (USP) was undertaken in response to the controversy regarding the exact nature of the contaminant involved in the heparin (HP) crisis. A mass balance analysis of the formulated drug product was performed. After freeze-drying, a 1-ml vial for injection afforded 54.8 ± 0.3 mg of dry solids. The excipients, sodium chloride and residual benzyl alcohol, accounted for 11.4 ± 0.5 and 0.9 ± 0.5 mg, respectively. Active pharmaceutical ingredient (API) represented 41.5 ± 1.0 mg, corresponding to 75.7 wt% of dry mass. Exhaustive treatment of API with specific enzymes, heparin lyases, and/or chondroitin lyases was used to close mass balance. HP represented 30.5 ± 0.5 mg, corresponding to 73.5 wt% of the API. Dermatan sulfate (DS) impurity represented 1.7 ± 0.3 mg, corresponding to 4.1 wt% of API. Contaminant, representing 9.3 ± 0.1 mg corresponding to 22.4 wt% of API, was found in the contaminated formulated drug product. The recovery of contaminant was close to quantitative (95.6–100 wt%). A single contaminant was unambiguously identified as oversulfated chondroitin sulfate (OSCS).     

Life cycle assessment of fine chemical production: a case study of pharmaceutical synthesis

Background, aim, and scope  

Pharmaceuticals have been recently discussed in the press and literature regarding their occurrence in rivers and lakes, mostly due to emissions after use. The production of active pharmaceutical ingredients (APIs) has been less analyzed for environmental impacts. In this work, a life cycle assessment (LCA) of the production of an API from cradle to factory gate was carried out. The main sources of environmental impacts were identified. The resulting environmental profile was compared to a second pharmaceutical production and to the production of basic chemicals.     

Impact of management practices on the tallgrass prairie

Summary The ELM ecosystem-level grassland model simulates the flow of water, heat, nitrogen, and phosphorus through the ecosystem and the biomass dynamics of plants, consumers, and the decomposers. This model was adapted to a tallgrass prairie site in northeastern Oklahoma, USA, the Osage Site of the U.S. International Biological Program Grassland Biome. Several range management manipulations were simulated by the model and the results compared to field data and literature information: (1) altering the grazing intensity, grazing system, and grazing time period; (2) adding nitrogen and phosphorus to the grassland; (3) adding water during the growing season; and (4) spring burning of the prairie.The model showed that cattle weight gain per head, above-ground and belowground plant production, transpiration water loss, standing dead biomass, and the net nitrogen balance decrease with increasing grazing intensity, while soil water content and bare soil water loss increase. A moderately stocked year-round cow-calf grazing system is more beneficial to the grassland than a more highly stocked seasonal steer grazing system because the former increases the aboveground and belowground primary production and the plant nutrient uptake rates. Range manipulations, such as fire, which stimulate uniform grazing of a pasture, increase primary production, cattle weight gains, and nutrient uptake of plants and animals. Model results indicated that adding fertilizer was the best strategy for increasing cattle weight gains per head, while adding water would produce the greatest increase in primary production. Simulation of yearly and triennial spring burns suggests that these treatments increase primary production, plant nutrient uptake, and cattle weight gain per head. Burning increases the nitrogen losses from the systems; however, these losses are greater with annual burns. The model results also suggest the spatial grazing pattern of cattle must be considered to correctly represent the impact of grazing on the prairie.The model is used to describe the behavior of the tallgrass prairie ecosystem, evaluate alternative management strategies, and identify future scientific research and management studies.     

Monitoring Blending of Pharmaceutical Powders with Multipoint NIR Spectroscopy

Blending of powders is a crucial step in the production of pharmaceutical solid dosage forms. The active pharmaceutical ingredient (API) is often a powder that is blended with other powders (excipients) in order to produce tablets. The blending efficiency is influenced by several external factors, such as the desired degree of homogeneity and the required blending time, which mainly depend on the properties of the blended materials and on the geometry of the blender. This experimental study investigates the mixing behavior of acetyl salicylic acid as an API and α-lactose monohydrate as an excipient for different filling orders and filling levels in a blender. A multiple near-infrared probe setup on a laboratory-scale blender is used to observe the powder composition quasi-simultaneously and in-line in up to six different positions of the blender. Partial least squares regression modeling was used for a quantitative analysis of the powder compositions in the different measurement positions. The end point for the investigated mixtures and measurement positions was determined via moving block standard deviation. Observing blending in different positions helped to detect good and poor mixing positions inside the blender that are affected by convective and diffusive mixing.     

Water relations in eggs of the lone star tick, Amblyomma americanum, with experimental work on the capacity for water vapor absorption

This study shows that water stress is not countered in eggs of the lone star tick, Amblyomma americanum (L.), using water vapor, and suggests involvement of liquid water as a developmental cue. Eggs fail to maintain an equilibrium water content in subsaturated air, hence, gain not equal to loss, with net water losses occurring at relative humidities near saturation and these eggs exhibit a three-fold drop in viability, but not incubation period, as compared to eggs held in saturated air. Amblyomma americanum eggs are stenohydric and feature low 58% water content, slow water losses <1%/h, and an impermeable chorion wherein the Arrhenius activation energy, Ea = -66J/K, is suppressed. Thus, enhancement of water retention, not water vapor absorption, permits eggs to resist desiccation.     

Surface Acidity and Solid-State Compatibility of Excipients with an Acid-Sensitive API: Case Study of Atorvastatin Calcium

The objectives of this study were to measure the apparent surface acidity of common excipients and to correlate the acidity with the chemical stability of an acid-sensitive active pharmaceutical ingredient (API) in binary API-excipient powder mixtures. The acidity of 26 solid excipients was determined by two methods, (i) by measuring the pH of their suspensions or solutions and (ii) the pH equivalent (pH_eq) measured via ionization of probe molecules deposited on the surface of the excipients. The chemical stability of an API, atorvastatin calcium (AC), in mixtures with the excipients was evaluated by monitoring the appearance of an acid-induced degradant, atorvastatin lactone, under accelerated storage conditions. The extent of lactone formation in AC-excipient mixtures was presented as a function of either solution/suspension pH or pH_eq. No lactone formation was observed in mixtures with excipients having pH_eq > 6, while the lactone levels were pronounced (> 0.6% after 6 weeks at 50°C/20% RH) with excipients exhibiting pH_eq < 3. The three pH_eq regions (> 6, 3–6, and < 3) were consistent with the reported solution pH-stability profile of AC. In contrast to the pH_eq scale, lactone formation did not show any clear trend when plotted as a function of the suspension/solution pH. Two mechanisms to explain the discrepancy between the suspension/solution pH and the chemical stability data were discussed. Acidic excipients, which are expected to be incompatible with an acid-sensitive API, were identified based on pH_eq measurements. The incompatibility prediction was confirmed in the chemical stability tests using AC as an example of an acid-sensitive API.

Electronic supplementary material

The online version of this article (doi:10.1208/s12249-014-0231-7) contains supplementary material, which is available to authorized users.KEY WORDS: acidity, atorvastatin, excipients, pH indicators, solid-state stability     

朝鲜蓟提取物颗粒剂的制备工艺研究

以单因素试验为基础，采用正交实验设计优化制备朝鲜蓟(Cynara scolymus)提取物颗粒剂的最佳工艺条件。以原料与辅料配比、原料药比例、乙醇浓度及干燥温度为考察因素，以颗粒合格率、溶化时间作为评价指标，采用L₉(3⁴)正交试验分别对颗粒合格率、溶化时间进行直观分析及方差分析。结果表明，最佳成型工艺为乳糖:糊精=3:1，乙醇浓度60%，原料药比例7.0%，干燥温度50 ℃。按此方案进行验证实验，颗粒性状良好，颗粒合格率为91.45%，含水量4.90%，减失重量不超过2.0%，溶解时间85.67 s，均符合2020年中国药典有关规定。通过正交试验优选的颗粒剂制备工艺稳定、简便易行，为朝鲜蓟提取物的剂型开发及工业化生产颗粒剂提供理论依据。     

Estimation of the starvation losses of nitrogen and energy in the rainbow trout (Oncorhynchus mykiss) with special regard to protein and energy maintenance requirements

Literature data are analysed regarding losses of body substances occurring during a period of food deprivation in rainbow trout ( Oncorhynchus mykiss ). Nitrogen (protein) and energy losses show a distinct dependence on fish mass (FM [g]) and water temperature (T [°C]). Several regression models for this relationship were compared with best testing estimates as follows:
Nitrogen loss [mg N 2 fish⁻¹ 2 d⁻¹] = 0.0658 e^(1.037) 2 FM^0.739
( n = 49, 9–20°C, 5–400g fish mass, P < 0.001, B = 0.826)
Nitrogen-corrected energy loss [J 2 fish⁻¹ 2 d⁻¹] = 22.09 e^(1.034) 2 FM^0.833
( n = 63, 9–25°C, 8–400 g fish mass, P < 0.001, B = 0.887).
For nitrogen loss as well as for nitrogen-corrected energy loss, the metabolic rate shows a progressive increase with rising water temperature. The temperature coefficient increases in magnitude as temperature increases. The introduction of a general common exponent (0.8 instead of 0.739 for nitrogen loss and 0.833 for energy loss) for fish mass decreases the precision of the estimate. The equations could serve as a base for estimating net protein and net energy maintenance requirements of rainbow trout. Possible limitations, caused by uncertainities in estimating the elevated metabolic rate by food intake and ingestion, are discussed.     

Towards Integrated Drug Substance and Drug Product Design for an Active Pharmaceutical Ingredient Using Particle Engineering

A novel experimental approach describing the integration of drug substance and drug production design using particle engineering techniques such as sonocrystallization, high shear wet milling (HSWM) and dry impact (hammer) milling were used to manufacture samples of an active pharmaceutical ingredient (API) with diverse particle size and size distributions. The API instability was addressed using particle engineering and through judicious selection of excipients to reduce degradation reactions. API produced using a conventional batch cooling crystallization process resulted in content uniformity issues. Hammer milling increased fine particle formation resulting in reduced content uniformity and increased degradation compared to sonocrystallized and HSWM API in the formulation. To ensure at least a 2-year shelf life based on predictions using an Accelerated Stability Assessment Program, this API should have a D [v, 0.1] of 55 μm and a D [v, 0.5] of 140 μm. The particle size of the chief excipient in the drug product formulation needed to be close to that of the API to avoid content uniformity and stability issues but large enough to reduce lactam formation. The novel methodology described here has potential for application to other APIs.     

Stability of Organoleptic Agents in Pharmaceuticals and Cosmetics

Organoleptic agents constitute an important niche in the field of pharmaceutical excipients. These agents encompass a range of additives responsible for coloring, flavoring, sweetening, and texturing formulations. All these agents have come to play a significant role in pharmaceuticals and cosmetics due to their ability to increase patient compliance by elevating a formulation’s elegance and esthetics. However, it is essential to review their physical and chemical attributes before use, as organoleptic agents, similar to active pharmaceutical ingredients (APIs), are susceptible to physical and chemical instability leading to degradation. These instabilities can be triggered by API-organoleptic agent interaction, exposure to light, air and oxygen, and changes in pH and temperature. These organoleptic agent instabilities are of serious concern as they affect API and formulation stability, leading to API degradation or the potential for manifestation of toxicity. Hence, it is extremely critical to evaluate and review the physicochemical properties of organoleptic agents before their use in pharmaceuticals and cosmetics. This literature review discusses commonly used organoleptic agents in pharmaceutical and cosmeceutical formulations, their associated instabilities, and probable approaches to overcoming them.     

Excipient Stability in Oral Solid Dosage Forms: A Review

The choice of excipients constitutes a major part of preformulation and formulation studies during the preparation of pharmaceutical dosage forms. The physical, mechanical, and chemical properties of excipients affect various formulation parameters, such as disintegration, dissolution, and shelf life, and significantly influence the final product. Therefore, several studies have been performed to evaluate the effect of drug-excipient interactions on the overall formulation. This article reviews the information available on the physical and chemical instabilities of excipients and their incompatibilities with the active pharmaceutical ingredient in solid oral dosage forms, during various drug-manufacturing processes. The impact of these interactions on the drug formulation process has been discussed in detail. Examples of various excipients used in solid oral dosage forms have been included to elaborate on different drug-excipient interactions.     

Diel aspects of the thermal structure and energy budget of a small English lake

SUMMARY. The did response of the thermal structure of Esthwaite Water to prevailing meteorological conditions was analysed for seven selected days, covering different phases of stratification. Meteorological measurements were combined with published empirical relations to compute 24-h thermal energy budgets for 2 days. Amplitudes of diel changes were controlled by the seasonal phase of stratification and the magnitude of incident solar radiation. Heat storage usually followed a sinusoidal curve with a minimum during the night and early morning and a maximum during the late afternoon. Wind-induced turbulent mixing, and vertical circulation induced by nocturnal cooling of the surface water through evaporative and conductive processes, also modified depth-time trends in thermal structure.
The budget accounted for almost all the thermal energy exchanges of the lake. Possible sources of a slight imbalance are considered. Although there was a positive daily surplus of net radiation, it may not always imply heat gain by the lake as it may be counter-balanced by heat losses through fluxes of latent and sensible heat, Net back-radiation was a major component of daily heat loss. The combined latent and sensible heat fluxes also accounted fora high proportion of heat loss to the atmosphere. Net flow of sensible heat to the lake was small but not always inappreciable. Net daily heat storage represented 26% (9 May) and 13% (17 June) of solar radiation Input. Advected energy due to lake inflow and outflow was negligible. Qualitative comparisons are made with long-term (seasonal and annual) energy budgets and heat fluxes.