Healthcare resource utilization patterns in psoriasis patients using biologic and conventional treatments in Finland.

Introduction and aim: Psoriasis vulgaris is associated with a significant healthcare burden, which increases over time as the disease progresses. The aim of this retrospective, population-based registry study was to characterize healthcare resource utilization (HCRU) in patients with psoriasis using biologics and oral immunosuppressants (conventionals) in Finland. Materials and methods: The study cohort included all patients with a diagnosis of psoriasis vulgaris in the secondary healthcare setting between 2012-2018, who initiated a biologic (n=1,297) or conventional (n=4,753) treatment between 2013-2017. Data on primary and secondary HCRU were collected from nationwide healthcare registries. Results: The results indicated a remarkable decrease in contacts with a dermatologist after the treatment initiation among patients starting biologic (mean annual number of contacts 5.4 per person before and 2.3 after the initiation), but not conventional (3.3 and 3.2) treatment. For conventional starters there was a high level of contacts with a dermatologist surrounding times of treatment switching, which was not observed for biologic starters. Conclusion: Overall, primary and other secondary care contacts did not decrease after the initiation or switch of treatment. The results highlight the importance of thorough consideration of the most optimal treatment alternatives, considering the overall disease burden to patients and healthcare systems.

Burden of idiopathic inflammatory rheumatic diseases in occupational healthcare: increased absenteeism and healthcare resource utilization.

OBJECTIVES: Patients with idiopathic inflammatory rheumatic diseases (IIRD) often have decreased working capacity resulting in indirect costs. However, data on patients' short-term sick leave has been limited. This retrospective cohort study evaluated the number and length of sick leave, including short-term leave, and occupational healthcare resource utilization (HCRU) of the working-aged patients with IIRD compared to controls. METHODS: The data on sick leave and occupational HCRU were gathered from the electronic medical records of the largest occupational healthcare provider in Finland from January 2012 to December 2019. Employed patients with an IIRD (including rheumatoid arthritis, spondyloarthritis, psoriatic and enteropathic arthritis, juvenile arthritis, and reactive arthritis) with at least a 12-months follow-up were identified and compared to age-, sex-, and follow-up matched controls without IIRD. RESULTS: Altogether 5405 patients with IIRD were identified and compared with an equal number of controls. The patients incurred approximately 2.5 times more sick leave than controls: 21.7 versus 8.5 days per patient year, respectively. Short-term sick leave was common: 83% of sickness absence periods of the patients lasted 1-9 days and represented 30% of the total absenteeism. Loss of productivity due to lost workdays was on average €4572 (95% confidence interval €4352-4804) per patient year. Occupational HCRU was approximately 1.8 times higher among IIRD patients than controls. CONCLUSIONS: Workers with an IIRD incur considerably more sick leave and use more occupational healthcare services than controls. Short sick leave not registered in national insurance registers constitute a significant portion of days off work among patients with IIRD.

Comorbidities and Medication Use in Finnish Patients with Psoriasis: A Population-Based Registry Study.

Therapeutic options for psoriasis vulgaris have changed during recent decades with the introduction of biologics. Few nationwide studies are available on psoriasis treatment patterns, and those from Finland predate the use of biologics. The aim of this retrospective, population-based registry study was to identify patients with psoriasis vulgaris and their treatment patterns in the secondary care setting in Finland. The study cohort included 41,456 adults with a diagnosis of psoriasis vulgaris in the public secondary healthcare setting from 2012 through 2018. Data on comorbidities, pharmacotherapy, and phototherapy were collected from nationwide healthcare and drug registries. Patients in the cohort had a wide range of comorbidities, with 14.9% having psoriatic arthritis. Treatment was based largely on topical and conventional systemic medications. Conventional medications were used by 28.9% of patients, and methotrexate was the most common option (20.9%). Biologics were used by 7.3% of patients, mostly as second- and third-line treatment. The use of conventional systemic medications, topical treatments, and phototherapy decreased after the initiation of biologics. This study of psoriasis vulgaris in Finland provides a framework for the development of future care practices.

Characterization of inflammatory bowel disease management by vedolizumab and concomitant treatments in real-life clinical practice.

Limited data is available on vedolizumab combination therapies in real-world clinical practice. Here, we evaluated the concomitant corticosteroid, immunosuppressive, and 5-aminosalicylic acid utilization of inflammatory bowel disease (IBD) patients treated with vedolizumab in a nationwide, retrospective, non-interventional, multi-centre chart review study. All adult patients from 27 Finnish gastroenterology centres with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) who had at least one vedolizumab infusion since it's availability in Finland were included in the study. Data were collected from medical charts at baseline (vedolizumab treatment initiation), week 14, and month 6. The majority of patients who used corticosteroids at the baseline and persisted on vedolizumab treatment for 6 months were taken off corticosteroid treatment by the 6-month time point (CD, 54.5%; UC, 69.8%). Modest corticosteroid dose reductions were observed among treatment persistent CD patients from the baseline until month 6. Corticosteroid users had less vedolizumab discontinuations due to primary ineffectiveness and more discontinuations due to adverse events than patients not using corticosteroids. Vedolizumab may have a corticosteroid sparing effect in real-world clinical practice. Concomitant corticosteroid use may lead to a lower rate of vedolizumab discontinuation due to primary ineffectiveness, but a higher discontinuation rate due to adverse events.

High treatment persistence rate and significant endoscopic healing among real-life patients treated with vedolizumab - a Finnish Nationwide Inflammatory Bowel Disease Cohort Study (FINVEDO).

OBJECTIVES: The efficacy and tolerability of vedolizumab in the treatment of inflammatory bowel diseases (IBD) has been demonstrated in an extensive GEMINI clinical trial programme. Clinical trials represent highly selected patient populations and, therefore, it is important to demonstrate effectiveness in real-life clinical practice. We set out to assess real-world treatment outcomes of vedolizumab in a nationwide cohort of treatment refractory Finnish Crohn's disease (CD) and ulcerative colitis (UC) patients. METHODS: This was a nationwide, retrospective, non-interventional, multi-centre chart review study. All adult patients from 27 Finnish gastroenterology centers with a diagnosis of UC or CD who had at least one vedolizumab infusion since the availability of the product in Finland, were included in the study. Data were collected retrospectively from medical charts at baseline, week 14, and month 6. The primary outcome measure was treatment persistence 24 weeks post-vedolizumab initiation. RESULTS: A total of 247 patients were included (108 CD, 139 UC). A total of 75.0% (n = 81) of all CD patients and 66.2% (n = 92) of all UC patients, were persistent on vedolizumab therapy for 6 months post treatment initiation. At month 6, 41.8% (28/67) of the treatment persistent CD patients and 73.3% (63/86) of the treatment persistent UC patients achieved clinical remission. Significant improvement in endoscopic scores were observed among treatment persistent patients (CD, n = 17, ΔSES-CD=-5.5, p = .008; UC, n = 26, ΔMayo endoscopic score =-0.5, p = .003) at month 6. CONCLUSIONS: Vedolizumab provides an effective and well-tolerated treatment option in real-world clinical practice even among treatment refractory IBD patients.

Amorphous solid dispersions of piroxicam and Soluplus(®): Qualitative and quantitative analysis of piroxicam recrystallization during storage.

The conversion of active pharmaceutical ingredient (API) from amorphous to crystalline form is the primary stability issue in formulating amorphous solid dispersions (SDs). The aim of the present study was to carry out qualitative and quantitative analysis of the physical solid-state stability of the SDs of poorly water-soluble piroxicam (PRX) and polyvinyl caprolactam-polyvinyl acetate-polyethylene-glycol graft copolymer (Soluplus(®)). The SDs were prepared by a solvent evaporation method and stored for six months at 0% RH/6 °C, 0% RH/25 °C, 40% RH/25 °C and 75% RH/25 °C. Fourier transform infrared spectroscopy equipped with attenuated total reflection accessory (ATR-FTIR) and Raman spectroscopy were used for characterizing the physical solid-state changes and drug-polymer interactions. The principal component analysis (PCA) and multivariate curve resolution alternating least squares (MCR-ALS) were used for the qualitative and quantitative analysis of Raman spectra collected during storage. When stored at 0% RH/6 °C and at 0% RH/25 °C, PRX in SDs remained in an amorphous form since no recrystallization was observed by ATR-FTIR and Raman spectroscopy. Raman spectroscopy coupled with PCA and MCR-ALS and ATR-FTIR spectroscopy enabled to detect the recrystallization of amorphous PRX in the samples stored at higher humidity.

Theophylline-nicotinamide cocrystal formation in physical mixture during storage.

Pharmaceutically relevant properties, such as solubility and dissolution rate, of active pharmaceutical ingredients can be enhanced by cocrystal formation. Theophylline and nicotinamide are known to form cocrystals, for example if subjected to solid-state grinding. However, under appropriate conditions, cocrystals can also form in physical mixtures without any mechanical activation. The purpose of this work was to study whether theophylline and nicotinamide could form cocrystals spontaneously, without mechanical activation. Crystalline theophylline and nicotinamide powders were gently mixed manually in a 1:1 molar ratio and stored at different relative humidity and temperature conditions. The solid state of the samples was analyzed by differential scanning calorimetry, Raman spectroscopy and X-ray powder diffractometry. Three different variations of theophylline were used as starting materials, e.g., two size fractions of theophylline anhydrate (large 710 µm-1 mm and small 180-355 µm), and monohydrate (recrystallized from water). As a reference, anhydrous theophylline-nicotinamide cocrystals were prepared by solid-state grinding. The results of this study indicate that theophylline-nicotinamide cocrystals can form without any mechanical activation from physical mixtures of theophylline and nicotinamide during storage. For anhydrous samples, storage humidity was found to be a critical parameter for cocrystal formation. Increasing temperature was also found to have an accelerating effect on the transformation. The effect of particle size of anhydrous theophylline on the transformation rate could not be completely resolved; DSC and Raman indicated slightly faster transformation with a physical mixture prepared from large size fraction of anhydrous theophylline, but the differences were only minor. Cocrystal formation was also observed in the physical mixture prepared from theophylline monohydrate, but the rate was not as high as with samples prepared from anhydrous material.

Unravelling the relationship between degree of disorder and the dissolution behavior of milled glibenclamide.

Milling is an attractive method to prepare amorphous formulations as it does not require the use of solvents and is suitable for thermolabile drugs. One of the key critical quality attributes of milled amorphous formulations is their dissolution behavior. However, there are limited studies that have investigated the relationship between degree of disorder induced by milling and dissolution behavior. The main aim of this study was to identify the analytical technique used to characterize degree of disorder that correlates best with the recrystallization behavior during dissolution of milled glibenclamide samples. Solid state and surface changes during dissolution of milled glibenclamide samples were monitored in order to elucidate the processes that influence the dissolution behavior of milled glibenclamide samples. Glibenclamide was ball milled for different durations and analyzed using X-ray powder diffractometry (XRPD), Raman spectroscopy and differential scanning calorimetry (DSC). Recrystallization during dissolution of the milled amorphous materials was investigated using an in situ Raman setup. SEM was used to monitor the surfaces of the compacts during dissolution. XRPD, Raman spectroscopy and DSC indicated that glibenclamide was fully amorphous after milling for 30, 60, and 120 min, respectively. 'DSC amorphous' (i.e. fully amorphous according to the onset of crystallization obtained from DSC) glibenclamide samples experienced negligible recrystallization which had no effect on the dissolution profiles. Samples that were not 'DSC amorphous' experienced recrystallization which resulted in a decrease in dissolution rate. Unexpected elevated dissolution rate was observed initially during dissolution for samples milled for 15 to 45 min, and this was related to particle loss from surfaces of the disks during dissolution. In conclusion, the onset of crystallization obtained from DSC best predicts the recrystallization of glibenclamide during dissolution. Recrystallization and particle loss from the surface of the dissolution should be considered when interpreting the dissolution data of milled glibenclamide samples.

Dissolution study of nanocrystal powders of a poorly soluble drug by UV imaging and channel flow methods.

Application of drug nanocrystals provides advantageous options for the pharmaceutical formulation development of poorly soluble drugs. The objective of this study was to investigate the dissolution behavior improving effects of differently sized nanocrystals of a poorly soluble model drug, indomethacin. Nanocrystal suspensions were prepared using a top-down wet milling technique with three stabilizers: poloxamer F68, poloxamer F127 and polysorbate 80. The dissolution of the differently sized indomethacin nanocrystals were investigated using a channel flow dissolution method and by UV imaging. Unmilled bulk indomethacin and physical mixtures were used as references. According to both the dissolution methods, the dissolution properties of indomethacin were improved by the particle size reduction. UV imaging was used for the first time as a dissolution testing method for fast dissolving nanoscale material. The technique provided new information about the concentration of the dissolved drug next to the sample surface; with the smallest nanocrystals (580 nm) the indomethacin concentration next to the particle surface exceeded five-fold the thermodynamic saturated indomethacin solution concentration. Thus the solubility improvement itself, not only the increased surface area for dissolution, may have an important role in the higher dissolution rates of nanocrystal formulations. Poloxamer F68 was the most optimal stabilizer in the preparation of the indomethacin nanocrystal suspensions and in the solubility and dissolution enhancement as well.

Modeling solid-state transformations occurring in dissolution testing.

Changes in the solid-state form can occur during dissolution testing of drugs. This can often complicate interpretation of results. Additionally, there can be several mechanisms through which such a change proceeds, e.g. solvent-mediated transformation or crystal growth within the drug material itself. Here, a mathematical model was constructed to study the dissolution testing of a material, which undergoes such changes. The model consisted of two processes: the recrystallization of the drug from a supersaturated liquid state caused by the dissolution of the more soluble solid form and the crystal growth of the stable solid form at the surface of the drug formulation. Comparison to experimental data on theophylline dissolution showed that the results obtained with the model matched real solid-state changes and that it was able to distinguish between cases where the transformation was controlled either by solvent-mediated crystallization or solid-state crystal growth.

Microscale freeze-drying with Raman spectroscopy as a tool for process development.

Until recently, the freeze-drying process and formulation development have suffered from a lack of microscale analytical tools. Using such an analytical tool should decrease the required sample volume and also shorten the duration of the experiment compared to a laboratory scale setup. This study evaluated the applicability of Raman spectroscopy for in-line monitoring of a microscale freeze-drying process. The effect of cooling rate and annealing step on the solid-state formation of mannitol was studied. Raman spectra were subjected to principal component analysis to gain a qualitative understanding of the process behavior. In addition, mannitol solid-state form ratios were semiquantitatively analyzed during the process with a classical least-squares regression. A standard cooling rate of 1 °C/min with or without an annealing step at -10 °C resulted in a mixture of α, ß, δ, and amorphous forms of mannitol. However, a standard cooling rate induced the formation of mannitol hemihydrate, and a secondary drying temperature of +60 °C was required to transform the hemihydrate form to the more stable anhydrous polymorphs. A fast cooling rate of 10 °C/min mainly produced δ and amorphous forms of mannitol, regardless of annealing. These results are consistent with those from larger scale equipment. In-line monitoring the solid-state form of a sample is feasible with a Raman spectrometer coupled microscale freeze-drying stage. These results demonstrate the utility of a rapid, in-line, low sample volume method for the semiquantitative analysis of the process and formulation development of freeze-dried products on the microscale.

In-line multipoint near-infrared spectroscopy for moisture content quantification during freeze-drying.

During the past decade, near-infrared (NIR) spectroscopy has been applied for in-line moisture content quantification during a freeze-drying process. However, NIR has been used as a single-vial technique and thus is not representative of the entire batch. This has been considered as one of the main barriers for NIR spectroscopy becoming widely used in process analytical technology (PAT) for freeze-drying. Clearly it would be essential to monitor samples that reliably represent the whole batch. The present study evaluated multipoint NIR spectroscopy for in-line moisture content quantification during a freeze-drying process. Aqueous sucrose solutions were used as model formulations. NIR data was calibrated to predict the moisture content using partial least-squares (PLS) regression with Karl Fischer titration being used as a reference method. PLS calibrations resulted in root-mean-square error of prediction (RMSEP) values lower than 0.13%. Three noncontact, diffuse reflectance NIR probe heads were positioned on the freeze-dryer shelf to measure the moisture content in a noninvasive manner, through the side of the glass vials. The results showed that the detection of unequal sublimation rates within a freeze-dryer shelf was possible with the multipoint NIR system in use. Furthermore, in-line moisture content quantification was reliable especially toward the end of the process. These findings indicate that the use of multipoint NIR spectroscopy can achieve representative quantification of moisture content and hence a drying end point determination to a desired residual moisture level.

Solid-state dependent dissolution and oral bioavailability of piroxicam in rats.

The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats. Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD). In addition, the effect of a new polymeric excipient Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated. Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam. Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium. Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats. Oral bioavailability of other two solid-state forms decreased in the order AH and MH. The use of Soluplus® was found to enhance the dissolution and oral bioavailability of piroxicam in rats. The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug.

An overview of recent studies on the analysis of pharmaceutical polymorphs.

Pharmaceutical solids are well known to be able to exist in different solid-state forms and there are a wide variety of solid-state analytical techniques available to characterize pharmaceutical solids and solid-state transformations. In this review, the commonly used solid-state analytical techniques, the type of information collected, and advantages and disadvantages of each technique are discussed, with the focus on their application in solid-state characterization and monitoring solid-state transformations, such as amorphization, crystallization, hydrate formation/dehydration and cocrystal formation. The information gathered from recent literature is compiled in various tables to aid the reader to get a quick overall picture about what type of phenomena have recently been studied and which analytical technique(s) have been used.

Taking PAT to the next level.

The International EuPAT4 Conference, organised by the EUFEPS QbD and PAT Sciences Network, was held in collaboration with the PROMIS Centre and University of Eastern Finland in Kuopio, Finland, on May 5-6, 2010. This high-quality meeting gathered the most significant experts in the field and almost one hundred participants from 14 countries, among them also many representatives from large international pharmaceutical companies.

Quantification of Process Induced Disorder in Milled Samples Using Different Analytical Techniques.

The aim of this study was to compare three different analytical methods to detect and quantify the amount of crystalline disorder/ amorphousness in two milled model drugs. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman spectroscopy were used as analytical methods and indomethacin and simvastatin were chosen as the model compounds. These compounds partly converted from crystalline to disordered forms by milling. Partial least squares regression (PLS) was used to create calibration models for the XRPD and Raman data, which were subsequently used to quantify the milling-induced crystalline disorder/ amorphousness under different process conditions. In the DSC measurements the change in heat capacity at the glass transition was used for quantification. Differently prepared amorphous indomethacin standards (prepared by either melt quench cooling or cryo milling) were compared by principal component analysis (PCA) to account for the fact that the choice of standard ultimately influences the quantification outcome. Finally, the calibration models were built using binary mixtures of crystalline and quench cooled amorphous drug materials. The results imply that the outcome with respect to crystalline disorder for milled drugs depends on the analytical method used and the calibration standard chosen as well as on the drug itself. From the data presented here, it appears that XRPD tends to give a higher percentage of crystalline disorder than Raman spectroscopy and DSC for the same samples. For the samples milled under the harshest milling conditions applied (60 min, sixty 4 mm balls, 25 Hz) a crystalline disorder/ amorphous content of 44.0% (XRPD), 10.8% (Raman spectroscopy) and 17.8% (DSC) were detected for indomethacin. For simvastatin 18.3% (XRPD), 15.5% (Raman spectroscopy) and 0% (DSC, no glass transition) crystalline disorder/ amorphousness were detected.

The Influence of Milling on the Dissolution Performance of Simvastatin.

Particle size reduction is a simple means to enhance the dissolution rate of poorly water soluble BCS-class II and IV drugs. However, the major drawback of this process is the possible introduction of process induced disorder. Drugs with different molecular arrangements may exhibit altered properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors, as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed by scanning electron microscopy (SEM) and image analysis. Process induced disorder was determined by partial least squares (PLS) regression modeling of respective X-ray powder diffractograms (XRPD) and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were milling frequency, milling time and ball quantity at a set drug load, out of which milling frequency was found to be the most important factor for particle size as well as process induced disorder. Milling frequency and milling time exhibited an interaction effect on the responses. The optimum milling settings using the maximum number of milling balls (60 balls with 4 mm diameter) was determined to be at a milling frequency of 21 Hz and a milling time of 36 min with a resulting primary particle size of 1.4 µm and a process induced disorder of 6.1% (assessed by Raman spectroscopy) and 8.4% (assessed by XRPD), at a set optimization limit of < 2 µm for particle size and < 10% for process induced disorder. This optimum was tested experimentally and the process induced disorder was determined to be 6.9% (± 2.2) by Raman spectroscopy and 7.8% (± 2.3) by XRPD. Subsequent intrinsic dissolution testing revealed that the process induced disorder was negligible with regard to the dissolution rate. The predicted primary particle size of 1.4 µm could be confirmed experimentally, but due to agglomeration of the primary particles a dissolution rate advantage was not shown, highlighting the importance of dissolution testing at an early stage of drug development.

Enhanced dissolution rate and synchronized release of drugs in binary systems through formulation: Amorphous naproxen-cimetidine mixtures prepared by mechanical activation.

Naproxen, a non-steroidal anti-inflammatory drug (NSAID), is a biopharmaceutics classification system (BCS) class II drug whose bioavailability is rate-limited by its dissolution. Cimetidine is sometimes co-administered with naproxen for the treatment of NSAID-induced gastro-intestinal disorders. Hence, there is interest in the design of new formulations that offer (1) concomitant release of both drugs, and (2) an enhanced dissolution rate of naproxen. This study investigates the formation of amorphous binary systems with naproxen and cimetidine. The binary mixtures of all tested molar ratios were found to become amorphous upon co-milling for 60 min at 4 degrees C. In contrast, pure naproxen could not be transformed to the amorphous state by mechanical activation. The 1:1 sample was the most physically stable when stored for 33 days at 40 degrees C, even though it did not have the highest T(g) when compared to the 1:2 sample. The 1:1 sample was further stored for 186 days and remained amorphous under all conditions. Raman spectroscopy suggested a 1:1 solid-state interaction between the imidazole ring of cimetidine and the carboxylic acid moiety of naproxen in the co-milled amorphous sample. Thus, the stabilization of the amorphous binary system is dictated by molecular-level interactions rather than bulk-level phenomena. No recrystallization of either drug in the 1:1 co-milled sample was observed during dissolution testing, with naproxen and cimetidine having a four and two times higher intrinsic dissolution rate, respectively, compared to their crystalline counterparts. Further, the release of the two drugs could be synchronized using this formulation approach.

Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation.

Co-milling of gamma-indomethacin and ranitidine hydrochloride form 2 at various weight ratios (1:2, 1:1 and 2:1) was investigated with a particular interest in the physicochemical properties and the stability of the milled mixed amorphous form. Co-milling was carried out using an oscillatory ball mill for various periods of time up to 60 min in a cold room (4 degrees C). The maximum temperature of the solid material was 42 degrees C during co-milling in a cold room. Results showed that both indomethacin and ranitidine hydrochloride were fully converted into the amorphous state after 60 min of co-milling. In contrast individually milled drugs remained partially crystalline after co-milling under the same conditions. During co-milling, the XRPD characteristic peaks of indomethacin were found to decrease faster than those of ranitidine hydrochloride. DSC results were in agreement with XRPD, and T(g)s of the fully converted amorphous mixtures of 29.3, 32.5 and 34.3 degrees C were measured for the 1:2, 1:1 and 2:1 mixtures, respectively. These T(g) values were in good agreement with the predicted T(g)s of the mixtures using the Gordon-Taylor equation. DRIFTS spectra of the co-milled amorphous samples showed peaks at 1610, 1679 and 1723 cm(-1), that were not present in the individually milled samples and that are indicative of an interaction at the carboxylic acid carbonyl (HO-C=O) and benzonyl amide (N=CO) of the indomethacin molecule with the aci-nitro (C=N) of ranitidine hydrochloride. Upon 30 days of storage, the 1:2 mixtures were found to crystallize; however, the amorphous 2:1 and 1:1 mixtures were stable when milled for 60 min and stored at 4 degrees C (for the 2:1 mixture) and at 4 and 25 degrees C (for the 1:1 mixture), respectively. Although XRPD, DSC and DRIFTS suggested an interaction between the two drugs, co-crystal formation was not observed between indomethacin and ranitidine hydrochloride.

Solid form screening--a review.

Solid form screening, the activity of generating and analysing different solid forms of an active pharmaceutical ingredient (API), has become an essential part of drug development. The multi-step screening process needs to be designed, performed and evaluated carefully, since the decisions made based on the screening may have consequences on the whole lifecycle of a pharmaceutical product. The selection of the form for development is made after solid form screening. The selection criteria include not only pharmaceutically relevant properties, such as therapeutic efficacy and processing characteristics, but also intellectual property (IP) issues. In this paper, basic principles of solid form screening are reviewed, including the methods used in experimental screening (generation, characterisation and analysis of solid forms, data mining tools, and high-throughput screening technologies) as well as basics of computational methods. Differences between solid form screening strategies of branded and generic pharmaceutical manufacturers are also discussed.