Publications by authors named "Jaakko Aaltonen"

31 Publications

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

Biologicals 2019 Mar 10;58:50-56. Epub 2019 Feb 10.

Department of Internal Medicine, Forssa Hospital, Forssa, Finland.

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.
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http://dx.doi.org/10.1016/j.biologicals.2019.01.007DOI Listing
March 2019

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

Scand J Gastroenterol 2018 Feb 19;53(2):158-167. Epub 2017 Dec 19.

b MedEngine Oy , Helsinki , Finland.

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.
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http://dx.doi.org/10.1080/00365521.2017.1416160DOI Listing
February 2018

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

Int J Pharm 2015 2;486(1-2):306-14. Epub 2015 Apr 2.

Department of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ijpharm.2015.03.079DOI Listing
February 2016

Theophylline-nicotinamide cocrystal formation in physical mixture during storage.

Int J Pharm 2015 20;486(1-2):121-30. Epub 2015 Mar 20.

School of Pharmacy, Pharmaceutical Technology, Faculty of Health Sciences, University of Eastern Finland, Kuopio Campus, Finland.

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.
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http://dx.doi.org/10.1016/j.ijpharm.2015.03.012DOI Listing
February 2016

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

Mol Pharm 2014 Jan 17;11(1):234-42. Epub 2013 Dec 17.

School of Pharmacy, University of Otago , Dunedin, New Zealand.

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.
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http://dx.doi.org/10.1021/mp4004145DOI Listing
January 2014

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

Eur J Pharm Sci 2013 Nov 30;50(3-4):511-9. Epub 2013 Aug 30.

Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejps.2013.08.030DOI Listing
November 2013

Modeling solid-state transformations occurring in dissolution testing.

Int J Pharm 2013 Apr 15;447(1-2):218-23. Epub 2013 Mar 15.

Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, 00014 University of Helsinki, Finland.

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.
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http://dx.doi.org/10.1016/j.ijpharm.2013.03.007DOI Listing
April 2013

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

Anal Chem 2013 Feb 4;85(4):2377-84. Epub 2013 Feb 4.

School of Pharmacy, Promis Centre, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

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.
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http://dx.doi.org/10.1021/ac303403pDOI Listing
February 2013

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

Anal Chem 2013 Feb 29;85(4):2109-16. Epub 2013 Jan 29.

School of Pharmacy, Promis Centre, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

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, β, 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.
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http://dx.doi.org/10.1021/ac3027349DOI Listing
February 2013

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

Eur J Pharm Sci 2013 Jan 22;48(1-2):47-54. Epub 2012 Oct 22.

Department of Pharmacy, Faculty of Medicine, University of Tartu, Nooruse 1, 50411 Tartu, Estonia.

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.
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http://dx.doi.org/10.1016/j.ejps.2012.10.005DOI Listing
January 2013

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

J Pharm Biomed Anal 2011 Jun 22;55(4):618-44. Epub 2010 Dec 22.

Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.

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.
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http://dx.doi.org/10.1016/j.jpba.2010.12.020DOI Listing
June 2011

The Influence of Milling on the Dissolution Performance of Simvastatin.

Pharmaceutics 2010 Dec 17;2(4):419-431. Epub 2010 Dec 17.

Solid State Group, School of Pharmacy, University of Otago, 18 Frederick Street, 9016 Dunedin, New Zealand.

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.
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http://dx.doi.org/10.3390/pharmaceutics2040419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967146PMC
December 2010

Taking PAT to the next level.

Eur J Pharm Sci 2011 Jan 30;42(1-2):1-2. Epub 2010 Oct 30.

Doramaxx Consulting, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.ejps.2010.10.009DOI Listing
January 2011

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

Pharmaceutics 2010 Feb 16;2(1):30-49. Epub 2010 Feb 16.

School of Pharmacy, University of Otago, 18 Frederick Street, 9016 Dunedin, New Zealand.

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.
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http://dx.doi.org/10.3390/pharmaceutics2010030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968347PMC
February 2010

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

J Control Release 2009 May 10;136(1):45-53. Epub 2009 Feb 10.

Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark.

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.
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http://dx.doi.org/10.1016/j.jconrel.2009.01.027DOI Listing
May 2009

Quantitative solid-state analysis of three solid forms of ranitidine hydrochloride in ternary mixtures using Raman spectroscopy and X-ray powder diffraction.

J Pharm Biomed Anal 2009 Jan 17;49(1):18-25. Epub 2008 Oct 17.

School of Pharmacy, University of Otago, Dunedin, New Zealand.

The aim of the study was to develop a reliable quantification procedure for mixtures of three solid forms of ranitidine hydrochloride using X-ray powder diffraction (XRPD) and Raman spectroscopy combined with multivariate analysis. The effect of mixing methods of the calibration samples on the calibration model quality was also investigated. Thirteen ternary samples of form 1, form 2 and the amorphous form of ranitidine hydrochloride were prepared in triplicate to build a calibration model. The ternary samples were prepared by three mixing methods (a) manual mixing (MM) and ball mill mixing (BM) using two (b) 5 mm (BM5) or (c) 12 mm (BM12) balls for 1 min. The samples were analyzed with XRPD and Raman spectroscopy. Principal component analysis (PCA) was used to study the effect of mixing method, while partial least squares (PLS) regression was used to build the quantification models. PCA score plots showed that, in general, BM12 resulted in the narrowest sample clustering indicating better sample homogeneity. In the quantification models, the number of PLS factors was determined using cross-validation and the models were validated using independent test samples with known concentrations. Multiplicative scattering correction (MSC) without scaling gave the best PLS regression model for XPRD, and standard normal variate (SNV) transformation with centering gave the best model for Raman spectroscopy. Using PLS regression, the root mean square error of prediction (RMSEP) values of the best models were 5.0-6.9% for XRPD and 2.5-4.5% for Raman spectroscopy. XRPD and Raman spectroscopy in combination with PLS regression can be used to quantify the amount of single components in ternary mixtures of ranitidine hydrochloride solid forms. Raman spectroscopy gave better PLS regression models than XRPD, allowing a more accurate quantification.
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http://dx.doi.org/10.1016/j.jpba.2008.09.054DOI Listing
January 2009

Solid form screening--a review.

Eur J Pharm Biopharm 2009 Jan 31;71(1):23-37. Epub 2008 Jul 31.

School of Pharmacy, University of Otago, Dunedin, New Zealand.

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.
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http://dx.doi.org/10.1016/j.ejpb.2008.07.014DOI Listing
January 2009

Influence of particle size and preparation methods on the physical and chemical stability of amorphous simvastatin.

Eur J Pharm Biopharm 2009 Jan 24;71(1):64-70. Epub 2008 Jul 24.

School of Pharmacy, University of Otago, Dunedin, New Zealand.

This study investigated the factors influencing the stability of amorphous simvastatin. Quench-cooled amorphous simvastatin in two particle size ranges, 150-180 microm (QC-big) and < or =10 microm (QC-small), and cryo-milled amorphous simvastatin (CM) were prepared, and their physical and chemical stability were investigated. Physical stability (crystallization) of amorphous simvastatin stored at two conditions was monitored by X-ray powder diffractometry (XRPD) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). Assessment of enthalpy relaxation of amorphous forms was conducted using DSC in order to link the physical and chemical stability with molecular mobility. Chemical stability was studied with high-performance liquid chromatography (HPLC). Results obtained from the current study revealed that the solubility of amorphous forms prepared by both methods was enhanced compared to the crystalline form. The rank of solubility was found to be QC-big=QC-small>CM>crystalline. For the physical stability, the highest crystallization rate was observed for CM, and the slowest rate was detected for QC-big, with an intermediate rate occurring for QC-small. QC exhibited lower molecular mobility and higher chemical degradation than CM. Therefore, the current study demonstrated that QC and CM have obvious differences in both physical and chemical properties. It was concluded that care should be taken when choosing preparation methods for making amorphous materials. Furthermore, particle size, a factor that has often been overlooked when dealing with amorphous materials, was shown to have an influence on physical stability of amorphous simvastatin.
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http://dx.doi.org/10.1016/j.ejpb.2008.07.010DOI Listing
January 2009

Simultaneous measurement of liquid-phase and solid-phase transformation kinetics in rotating disc and channel flow cell dissolution devices.

Int J Pharm 2008 Nov 15;363(1-2):66-72. Epub 2008 Jul 15.

Division of Pharmaceutical Technology, University of Helsinki, Helsinki, Finland.

Solvent-mediated solid-phase transformations may occur during dissolution tests which complicates the evaluation of dissolution rates in cases of metastable drugs. The purpose of this study was to determine the effects of solvent-mediated transformations of theophylline anhydrate (TP (A)) on the intrinsic dissolution rate in simulated gastric fluid at pH 1.2. A combined method set-up for simultaneous measurement of the dissolved quantity of drug and the solid form composition was constructed from in situ Raman spectroscopy and UV-vis-spectrophotometry. Transformation kinetics in the traditional USP rotating disc (RD) dissolution apparatus was compared with the recently introduced channel flow cell (CFC). Solid-phase data, supported by scanning electron micrographs taken off-line, explained the changes in the intrinsic dissolution rates due to hydrate formation. Kinetic modelling showed that first order kinetics fitted the data in CFC, but the conversion in RD was strongly S-shaped. These differences were related to dissimilar hydrodynamic conditions and diffusion characteristics in the two dissolution testing devices. In situ solid-phase measurement during dissolution testing can largely improve the understanding of the dissolution results of metastable drugs. This information is valuable in drug candidate selection as well as in explaining and controlling the behaviour of drug substances in the final drug products.
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http://dx.doi.org/10.1016/j.ijpharm.2008.07.001DOI Listing
November 2008

Solvent-mediated solid phase transformations of carbamazepine: Effects of simulated intestinal fluid and fasted state simulated intestinal fluid.

J Pharm Sci 2009 Mar;98(3):985-96

Division of Pharmaceutical Technology, P.O. Box 56, FI-00014, University of Helsinki, Finland.

Solvent-mediated transformations of carbamazepine (CBZ) anhydrate form III were investigated in Simulated Intestinal Fluid, a simple USP buffer medium, and in FaSSIF, which contains sodium taurocholate (STC) and lecithin, important surfactants that solubilize lipophilic drugs and lipids in the gastrointestinal tract. Raman spectroscopy (in situ) was utilized to reveal the connection between the changes in solid phase composition and dissolution rate while simultaneously detecting the solid state and the dissolved amount of CBZ. Initial dissolution rate was clearly higher in FaSSIF, while the solid phase data revealed that the crystallization of CBZ dihydrate was inhibited in both the dissolution media, albeit by different mechanisms. In SIF this inhibition was related to extensive needle growth, which impeded medium contact with the solid surface by forming a sterical barrier leading to retarded crystallization rates. Morphological changes from the needle-like dihydrate crystals to plate-like counterparts in FaSSIF, combined with the information that the transformation process was leveled off, evidenced strong hydrogen bonding behavior between the CBZ and STC molecules. These results underline the importance of biologically representative dissolution media in linking the in vitro dissolution results of solids that are capable of hydrate formation to their in vivo dissolution behavior.
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http://dx.doi.org/10.1002/jps.21490DOI Listing
March 2009

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

Eur J Pharm Biopharm 2009 Jan 3;71(1):47-54. Epub 2008 Jul 3.

School of Pharmacy, University of Otago, Dunedin, New Zealand.

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.
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http://dx.doi.org/10.1016/j.ejpb.2008.06.022DOI Listing
January 2009

Perspectives in the use of spectroscopy to characterise pharmaceutical solids.

Int J Pharm 2008 Dec 8;364(2):159-69. Epub 2008 May 8.

School of Pharmacy, University of Otago, New Zealand.

Knowledge of the solid-state properties is one of the key issues in understanding the performance of drugs. Recent developments in spectroscopic techniques have made them popular tools for solid phase analysis; they are fast, accurate and suitable for real-time measurements during processing, and further, they can be used to obtain structural understanding of solid forms, for example, by the use of multivariate analysis and computational chemistry. In this article emerging topics related to spectroscopic analysis of pharmaceutical solids are reviewed. The following areas are highlighted: (1) the importance of multivariate methods in the analysis of solid forms when using spectroscopic techniques, (2) spectroscopic analysis of processing-induced solid phase transformations in the manufacturing setting, (3) novel spectroscopic techniques and pharmaceutical examples of their use, and (4) the advantages and the use of computational simulation of vibrational spectra. The topics listed are thought to be of the foremost importance in improving the understanding of pharmaceutical materials, processes and formulations.
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http://dx.doi.org/10.1016/j.ijpharm.2008.04.043DOI Listing
December 2008

Establishing quantitative in-line analysis of multiple solid-state transformations during dehydration.

J Pharm Sci 2008 Nov;97(11):4983-99

Division of Pharmaceutical Technology, University of Helsinki, Finland.

The aim of the study was to conduct quantitative solid phase analysis of piroxicam (PRX) and carbamazepine (CBZ) during isothermal dehydration in situ, and additionally exploit the constructed quantitative models to analyze the solid-state forms in-line during fluidized bed drying. Vibrational spectroscopy (near-infrared (NIR), Raman) was employed for monitoring the dehydration and the quantitative model was based on partial least squares (PLS) regression. PLS quantification was confirmed experimentally using isothermal thermogravimetric analysis (TGA) and X-ray powder diffractometry (XRPD). To appraise the quality of quantitative models several model parameters were evaluated. The hot-stage spectroscopy quantification results were found to be in reasonable agreement with TGA and XRPD results. Quantification of PRX forms showed complementary results with both spectroscopic techniques. The solid-state forms observed during CBZ dihydrate dehydration were quantified with Raman spectroscopy, but NIR spectroscopy failed to differentiate between the anhydrous solid-state forms of CBZ. In addition to in situ dehydration quantification, Raman spectroscopy in combination with PLS regression enabled in-line analysis of the solid-state transformations of CBZ during dehydration in a fluidized bed dryer.
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http://dx.doi.org/10.1002/jps.21357DOI Listing
November 2008

Solvent diversity in polymorph screening.

J Pharm Sci 2008 Jun;97(6):2145-59

Department of Pharmaceutics and Analytical Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.

Selecting a diverse set of solvents to be included in polymorph screening assignments can be a challenging task. As an aid to decision making, a database of 218 organic solvents with 24 property descriptors was explored and visualized using multivariate tools. The descriptors included, among others, log P, vapor pressure, hydrogen bond formation capabilities, polarity, number of pi-bonds and descriptors derived from molecular interaction field calculations (e.g., size/shape parameters and hydrophilic/hydrophobic regions). The data matrix was initially analyzed using principal component analysis (PCA). Results from the PCA showed 57% cumulative variance being explained in the first two principal components (PCs), although relevant information was also found in the third, fourth and fifth component, revealing distinct clusters of solvents. Since five dimensions were not suitable for visual presentation, a nonlinear method, self-organizing maps (SOMs), was applied to the dataset. The constructed SOM displayed features of clusters observed in the first three PCs, however in a more compelling way. Thus, the SOM was chosen as the visually most convenient way to display the diversity of the 218 solvents. In addition, it was demonstrated how safety aspects can be considered by labeling a large fraction of the solvents in the SOM with toxicological information.
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http://dx.doi.org/10.1002/jps.21153DOI Listing
June 2008

Solid-state properties and relationship between anhydrate and monohydrate of baclofen.

J Pharm Sci 2007 Sep;96(9):2399-408

Division of Pharmaceutical Technology, Faculty of Pharmacy, P.O. Box 56 University of Helsinki, FI-00014 Helsinki, Finland.

Baclofen, a widely used antispastic agent, has been found to exist in two crystalline forms, the anhydrate and monohydrate. The aim of this study was (1) to identify and characterize these two solid phases of baclofen, and (2) to examine the processing-induced phase transformations associated with wet granulation of baclofen. Using multiple techniques (powder X-ray diffraction, thermal analysis, vibrational spectroscopy and water vapor sorption analysis), a structural relationship has been established between the anhydrate and monohydrate of baclofen. Thermal and variable-temperature powder X-ray diffraction data indicate that the monohydrate, which presumably belongs to the channel hydrate class, dehydrates at 60 degrees C with the formation of the anhydrate. Furthermore, the anhydrate to monohydrate transformation followed by optical microscopy was found to occur via a solvent-mediated route. During wet massing experiments, the critical moisture value for the hydrate formation under the conditions of the present study was identified using qualitative powder X-ray diffraction and Raman spectroscopy. Finally, the interconversion pathway between the two crystalline forms of baclofen was presented. The knowledge of this pathway provides better understanding and control of the solid state of baclofen during processing and storage.
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http://dx.doi.org/10.1002/jps.20894DOI Listing
September 2007

Hyphenated spectroscopy as a polymorph screening tool.

J Pharm Biomed Anal 2007 Jun 13;44(2):477-83. Epub 2007 Feb 13.

Division of Pharmaceutical Technology, P.O. Box 56, 00014 University of Helsinki, Finland.

Polymorph screening of a model compound (nitrofurantoin) was performed. Nitrofurantoin was crystallized from acetone-water mixtures with varying process parameters. Two anhydrate forms (alpha and beta) and one monohydrate form (II) were crystallized in the polymorph screen. The solid forms were analyzed with three complementary spectroscopic techniques: near-infrared (NIR) spectroscopy, Raman spectroscopy and terahertz pulsed spectroscopy (TPS), and the results of the solid phase analysis were verified with X-ray powder diffraction (XRPD). NIR and Raman spectroscopy were coupled to achieve a rapid and comprehensive method of solid phase analysis. The hyphenated NIR/Raman spectroscopic data were analyzed with a multivariate method, principal component analysis (PCA). The combination was found effective in screening solid forms due to the complementary characteristics of the methods. NIR spectroscopy is powerful in differentiating between anhydrate and hydrate forms and intermolecular features, whereas Raman spectroscopy is sensitive to intramolecular alterations in the molecular backbone.
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http://dx.doi.org/10.1016/j.jpba.2007.02.009DOI Listing
June 2007

Qualitative in situ analysis of multiple solid-state forms using spectroscopy and partial least squares discriminant modeling.

J Pharm Sci 2007 Jul;96(7):1802-20

Division of Pharmaceutical Technology, University of Helsinki, Helsinki, Finland.

This study used in situ spectroscopy to reveal the multiple solid-state forms that appear during isothermal dehydration. Hydrate forms of piroxicam and carbamazepine (CBZ) were investigated on hot-stage at different temperatures using near-infrared (NIR) and Raman spectroscopy combined with multivariate modeling. Variable temperature X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and Karl Fisher titrimetry were used as reference methods. Partial least squares discriminant analysis (PLS-DA) was performed to qualitatively evaluate the phase transition. It was shown that the constructed PLS-DA models, where spectral differences were directly correlated to solid-state modifications, enabled differentiation between the multiple forms. Qualitative analysis revealed that during dehydration, hydrates, such as CBZ dihydrate, may go through several solid-state forms, which must be considered in quantitative model construction. This study demonstrates that in situ analysis can be used to monitor the dehydration and reveal associated solid-state forms prior to quantification. The utility of the complementary spectroscopic techniques, NIR and Raman, have been shown.
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http://dx.doi.org/10.1002/jps.20840DOI Listing
July 2007

Drug hydrate systems and dehydration processes studied by terahertz pulsed spectroscopy.

Int J Pharm 2007 Apr 21;334(1-2):78-84. Epub 2006 Oct 21.

TeraView Ltd., St John's Innovation Park, Cambridge CB4 0WS, United Kingdom.

Terahertz pulsed spectroscopy was used to distinguish between different hydrate systems. In the example of four pharmaceutical materials lactose, carbamazepine, piroxicam and theophylline it was demonstrated that all different hydrate and anhydrate forms exhibit distinct spectra in the far infrared. Furthermore the dehydration of theophylline monohydrate was characterised in situ. Here, a phase transition from the monohydrate to the anhydrous form was observed, followed by evaporation of the hydrate water in a second step. The rotational spectrum of water vapour is very characteristic in the far infrared and can easily be discerned from the terahertz spectrum of the solid state form.
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http://dx.doi.org/10.1016/j.ijpharm.2006.10.027DOI Listing
April 2007

Influence of polymorphic form, morphology, and excipient interactions on the dissolution of carbamazepine compacts.

J Pharm Sci 2007 Mar;96(3):584-94

School of Pharmacy, University of Otago, P.O. Box 913, Dunedin, New Zealand.

To gain a deeper understanding of the behavior of carbamazepine (CBZ) and CBZ dihydrate (DH) compacts during in vitro dissolution tests various factors were investigated: hydrate formation of CBZ, crystal morphology, surface area, and excipient influence. Dissolution tests were performed in three different dissolution media: distilled water, hydroxypropyl methylcellulose (HPMC), and polyethylene glycol (PEG) solutions. For the CBZ compacts, the dissolution rate of CBZ in water was fastest (0.338 mg L(-1) min(-1)). With increasing ability of the excipients to inhibit the hydration of CBZ (PEG < HPMC), surprisingly the dissolution rate of CBZ compacts decreased: PEG solution (0.314 mg L(-1) min(-1)) > HPMC solution (0.257 mg L(-1) min(-1)). This implies that DH formation resulted in an apparent increase in the dissolution rate rather than slowing it down. For the DH compacts, the dissolution rate in water (0.055 mg L(-1) min(-1)) was slower than that of PEG and HPMC solutions (0.174 and 0.178 mg L(-1) min(-1), respectively). The contact angle measurements showed a significantly higher value in water (61.0 degrees) than in PEG and HPMC solutions (44.8 degrees and 43.1 degrees, respectively). Although the dissolution of CBZ and DH compacts in various dissolution media are complex processes, the influence and relative importance of these factors were clearly detected providing better understanding of the dissolution behavior of the drug.
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http://dx.doi.org/10.1002/jps.20756DOI Listing
March 2007

In situ measurement of solvent-mediated phase transformations during dissolution testing.

J Pharm Sci 2006 Dec;95(12):2730-7

Division of Pharmaceutical Technology, P.O. Box 56, 00014 University of Helsinki, Finland.

In this study, solvent-mediated phase transformations of theophylline (TP) and nitrofurantoin (NF) were measured in a channel flow intrinsic dissolution test system. The test set-up comprised simultaneous measurement of drug concentration in the dissolution medium (with UV-Vis spectrophotometry) and measurement of the solid-state form of the dissolving solid (in situ with Raman spectroscopy). The solid phase transformations were also investigated off-line with scanning electron microscopy. TP anhydrate underwent a transformation to TP monohydrate, and NF anhydrate (form beta) to NF monohydrate (form II). Transformation of TP anhydrate to TP monohydrate resulted in a clear decrease in the dissolution rate, while the transformation of NF anhydrate (form beta) to NF monohydrate (form II) could not be linked as clearly to changes in the dissolution rate. The transformation of TP was an order of magnitude faster than that of NF. The presence of a water absorbing excipient, microcrystalline cellulose, was found to delay the onset of the transformation of TP anhydrate. Combining the measurement of drug concentration in the dissolution medium with the solid phase measurement offers a deeper understanding of the solvent-mediated phase transformation phenomena during dissolution.
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http://dx.doi.org/10.1002/jps.20725DOI Listing
December 2006
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