Green Synthesis of Ibuprofen–Nicotinamide Cocrystals and In-Line

Feb 27, 2013 - The use of safer solvents and in-line monitoring are some of the green chemistry principles that should be evaluated in environmentally...
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Green Synthesis of Ibuprofen-Nicotinamide Cocrystals and In-line evaluation by Raman Spectroscopy Frederico Luis Felipe Soares, and Renato Lajarim Carneiro Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg3017112 • Publication Date (Web): 27 Feb 2013 Downloaded from http://pubs.acs.org on February 28, 2013

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Green Synthesis of Ibuprofen-Nicotinamide Co-crystals and In-line evaluation by Raman Spectroscopy Frederico L. F. Soares*, Renato L. Carneiro Federal University of São Carlos, Department of Chemistry, BR-13560 São Carlos, SP, Brazil

[email protected] Abstract Pharmaceuticals co-crystals are mixed crystals that contain two or more different molecular components. These crystals usually present different characteristics from their precursor, an improvement in the drug solubility being the most important property. This article is the first to report a green synthesis of ibuprofen-nicotinamide co-crystal in aqueous media. The use of safer solvents and in-line monitoring are some of the green chemistry principles that should be evaluated in environmentally correct synthesis. The Raman spectroscopy as a PAT tool provided an effective in line method to monitor and quantify the reaction. This is the first report of the co-crystal of ibuprofen-nicotinamide obtained by slurry conversion. A total conversion of the initial substrates into the co-crystal was obtained in mild conditions. The use of chemometric tools and Raman spectroscopy made it possible to monitor and understand the cocrystallization mechanism, and the synthesis provided.

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Introduction Co-crystals are crystalline structures of different molecules that combined together forms a unique crystal pattern, different from the precursor compounds1, 2. They differ from the solvates because at room temperature all their co-formers are in the solid state3, 4

and diverge from the salts since no proton transfer occurs on the co-crystal formation3,

4

. Co-crystals usually present physical and chemical properties different from the

original raw materials, such as: solubility, melting point, chemical interaction, stability and bioavailability5. These changes in properties, compared to its precursors, make industries and pharmaceutical research even more interested in this new class of compounds, mainly in order to improve the solubility and the bioavailability of a few active pharmaceutical ingredients with low solubility. Pharmaceutical co-crystals are a type of co-crystal, which at least one of the components is an active pharmaceutical ingredient (API) and the other one is called co-former. The API and the co-former are linked by intermolecular interaction, such as hydrogen bonding, Van der Waals force and π–π interaction6. According to the Biopharmaceutical Classification System (BCS), Ibuprofen is a class II nonsteroidal anti-inflammatory drug, that presents high permeability but low solubility in water7. The addition of soluble molecules in the crystalline array of the ibuprofen has been an alternative to improve its solubility, and therefore its bioavailability8. A co-crystal widely studied is ibuprofen-nicotinamide (IBP-NCT). The central part of the crystallographic motif is a dimer of nicotinamide, in which a homosynthon formation occurs between the amides of each molecule. The ibuprofen forms a heterosynthon interaction between its carboxylic acid and the pyridinic ring of the nicotinamide9 (Figure 1). 2 ACS Paragon Plus Environment

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Figure 1.Ibuprofen-nicotinamide co-crystal (IBP-NCT) The most common methods applied to form this co-crystal are slow evaporation8-11, melting method monitored by hot-stage microscopy11, forced evaporation12,

13

and

mechanochemical methods14, 15. Although slurry-crystallization is a method widely used to form pharmaceutical co-crystals13, 14, there are no reports of using this method to produce the co-crystal of ibuprofen-nicotinamide. Focusing on this type of co-crystal, we attempted to seek out new synthetic routes following the green chemistry principles with an objective to generate less hazardous residuals. The green chemistry is based on the development of chemical products with less toxicity and no byproducts, without decreasing the efficiency. Anastas and Warner summarized 12 principles that must be evaluated in the green synthesis16, among these, the use of safer solvents and real time analysis of the chemical process have been increasingly studied. The formation of ibuprofen-nicotinamide co-crystal in water, by the slurrycrystallization method, provides a series of advantages within the green chemistry principles, which can be highlighted: real time analysis by Raman spectroscopy (since water practically does not generate Raman scattering) as PAT tool; use of safer solvents and; the prevention of concomitant formation of other crystalline forms. Under the green chemistry, the in-line monitoring of chemical reactions are essential to control and observe the presence of byproducts that may be hazardous to human 3 ACS Paragon Plus Environment

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health. Another factor that corroborates the use of the process analytical technology (PAT) in green chemistry is a decrease in time process. With a reduced amount of cycling time it is possible to obtain the same product with lower energy consumption, that in the long term benefits industry as well as the environment. Other principles also important in green chemistry that can be related to this synthesis are:



Prevention: The co-crystallization reaction does not generate residuals



Atom economy: All materials incorporated in the process are presented in the final product



Design for energy efficiency: The best yield was obtained at 60 °C, a reasonable temperature, mainly when compared to the ibuprofen-nicotinamide co-crystal patent, that uses an extruder at 90 °C17

The American FDA agency (Food and Drug Administration) recommends the pharmaceutical companies to employ the system of process analytical technology (PAT) to monitor their physical or chemical process18. The PAT is based on the use of process analyzers (like probes) allied to multivariate tools, to obtain real time information. Some of the PAT objectives are19: to understand the mechanisms involved in the process and decrease the failures; find the end point of the reaction, reducing the batch time and increasing the process efficiency; enable a more accurate analysis of the experimental design, with reliable and precise information. In 2012 Kelly et. al. performed an off-line monitoring on the formation of ibuprofennicotinamide co-crystal using a heated extruder and NIR spectroscopy15. This is the first work with IBP-NCT co-crystal with emphasis on PAT. An important PAT tool is the chemometric analysis for multivariate data mining. In reaction monitoring using spectroscopy methods, the data can be organized in a matrix.

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The rows are correspondent to the spectra obtained at different times. The columns are the wavelengths of each spectrum. The MCR-ALS (multivariate curve resolution) is based on a bilinear decomposition of the original data (D) in two separated matrices20 (Equation 1) using a deconvolution of overlapping spectra. Through the iterative method of least squares regression it is possible to obtain a matrix correspondent to a concentration profile (C), one correspondent to a spectra profile (S) of each k-component present in the original data and a residual matrix (E) containing the information that is not explained by the model. Applying the MCR-ALS it is possible to monitor the co-crystallization process as well as its starting materials. With the concentration profile, resulting from the decomposition it is possible to detect the quantity of each component presented in the reaction, and easily obtain the end point of the process. The multivariate curve resolution (MCR-ALS) enables one to obtain concentration profiles of each component presented in the reaction, since the higher the concentration of a species, the higher its contribution to the total signal (D)21: Dk = CkST + Ek

(1)

The present work aims to propose and monitor a green synthesis of ibuprofennicotinamide co-crystal. Employing chemometric tools and PAT it is possible to obtain valuable information such as co-crystallization mechanisms and to determine the end point of the reaction. Materials and Methods Reagents Ibuprofen was purchased from IOL Chemicals and Pharmaceuticals Ltd. and the nicotinamide from Aarti Drugs Limited. The methanol was purchased from Quemis, P.A. grade.

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The experimental procedure was divided in two parts. The first one is referent to the synthesis and characterization of co-crystal by slow evaporation. The other is the synthesis and monitoring of the slurry-crystallization Synthesis of ibuprofen-nicotinamide by slow evaporation To obtain a reference of the IBP-NCT co-crystal, a well-established synthesis was conducted that produced a high degree of purity. Approximately 618.8 mg of ibuprofen (3 mmol) and 366.4 mg of nicotinamide (3 mmol) was placed in a beaker and dissolved in 3 mL of methanol. The co-crystal of IBP-NCT was grown when all the solvent was evaporated (approximately 10 hours). The co-crystal was heated in an oven at 40 °C for 12 hours to remove the residual solvent. The product was characterized by Raman spectroscopy and XRPD. The Raman spectrum was used as the initial estimate and equality constraint on the spectra profile during the MCR-ALS analysis.

Synthesis of ibuprofen-nicotinamide by slurry reaction Approximately 412.5 mg of ibuprofen (2 mmol) was placed in a beaker. In another recipient, a solution of nicotinamide near saturation (5 mol L-1) was prepared. For this, 244.3 mg of nicotinamide (2 mmol) was solubilized in 400 µL of deionized water. The nicotinamide solution was added to the beaker containing the ibuprofen. The reaction was heated on an IKA heating plate, model C-MAG HS 7, with magnetic stirrer and electronic thermometer. This procedure was carried out at three different temperatures: room temperature (23 °C ± 1 °C), 40 °C (± 2 °C) and 60 °C (± 3 °C). Monitoring occurred during a period of 5 hours for the room temperature reaction, and 6 hours for the others. The spectra were obtained with a spectral range of 586 – 1137 cm-1, with 2 minutes of delay between each spectrum, resulting in a matrix of 181 rows and 336 columns. The MCR-ALS

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deconvolution was applied into the original data matrix, resulting in a concentration profile, which allowed the reaction monitoring. Figure 2 is a scheme of the experimental procedure.

Figure 2.Scheme of the experimental procedure of the reaction monitoring X-ray powder diffraction (XRPD) The purity of the co-crystal obtained by slow evaporation was analyzed by X-ray powder diffraction using a Rigaku Multiflex diffractometer with wavelength of 0.154 nm, Cu source, voltage of 40 kV and current of 30 mA. The sample were scanned from 5° to 45° (2θ) using a step of 0.2° θ/minute. In-line Raman spectroscopy For the in-line monitoring, a B&W Tek i-Raman BWS 415-785H was used, with a red laser (785 nm), spectral resolution of 2.2 cm-1. The spectra were recorded with a probe located above the reaction. Each spectrum was obtained with 120 seconds of acquisition, which is also the delay time of each spectrum. The spectral range between

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281 and 1708 cm-1 (Raman Shift) and the laser power was varied from 224 mW to 320 mW, each spectrum was then normalized to 100% of the laser power (320 mW) Chemometric methods At the end of the reactions, the data generated by Raman spectroscopy were stored in a matrix. The spectra were derived (in some cases), normalized and smoothed by PCA (principal components analysis). The smoothing by PCA has as an objective to reduce the instrumental noise without losing spectral information. An X matrix can be recovered by the product of n scores (tn) by n loadings (pnT), whereas n is the number of principal components necessary to explain almost all the original data. In this case, there are three different substances involved, therefore three principal components. For the smoothing by PCA 6 principal components were used to ensure that all the spectral information was maintained. The ALS routine was used on the MCR_ALS toolbox21. The MCR-ALS was used in the following conditions: •

Spectra range: 586 – 1137 cm-1;



Three components;



Initial estimate: pure spectra of ibuprofen, nicotinamide and co-crystal;



Non-negativity on concentration profile;



Non-negativity on spectra profile (only on the spectra that were not derived);



Equality constraint on the spectra profile;

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Figure 3. Graphical representation of the MCR-ALS in the monitoring data. Results and discussion Characterization of the standard co-crystal The co-crystal, synthetized by slow evaporation, was characterized by XRPD (Figure 4) and Raman spectroscopy (Figure 5). Comparing the co-crystal pattern with it coformer, it is possible to observe that no other crystalline form appears on the diffractogram of the co-crystal, besides the co-crystal itself. The peaks at 6.10 and 12.24 2°θ, which are characteristics of the ibuprofen, are absent in the diffractogram of the cocrystal, as are the characteristic peak of nicotinamide, 14.8 2°θ. A formation of a new crystalline structure can be confirmed by the significant changes in the co-crystal diffractogram pattern. Its pattern differs from the pattern of an ibuprofen and nicotinamide mixture. 0.4 0.35 Relative Intensity (counts)

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0.3 0.25

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Figure 4. XRPD patterns of the co-crystal (C) synthetized by slow evaporation and its co-formers (A - ibuprofen; B - nicotinamide)11. The co-crystal Raman spectrum also differs from the pure spectra of its co-former, as presented in Figure 5. In the nicotinamide spectra, the most evident change is the peak shift at 1039 cm-1, relative to C-N-H stretch22. This change is due to the homosynthon

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interaction that occurs between two nicotinamide molecules, in the co-crystal motif. In the region between 1570 – 1630 cm-1 shifts in the nicotinamide peaks can be noted. This region is relative to the pyridinic ring stretch, where the ibuprofen molecule can execute the heterosynthon interaction. The co-crystal spectrum maintains various peaks from the ibuprofen spectrum, mainly in the region between 900 – 1500 cm-1, characteristic of CH2 and CH3 wags22. However, it is possible to differentiate the ibuprofen spectrum from the co-crystal spectrum in two specific regions: in the 746 cm-1 and between 820 – 850 cm-1. The peak in 746 cm-1, relative to C=O and aromatic C-H stretch23 presented in the ibuprofen spectrum is absent in the co-crystal spectrum. This peak, selective to ibuprofen, can be an indicator of the degree of purity of the co-crystal. Between 820 – 850 cm-1there is a shift in the peaks relative to aromatic C-H, the peak at 833 cm-1 being the most evident for the ibuprofen23. 0.8 0.7

Relative Intensity (counts)

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Figure 5. Raman spectra of the co-crystal (C) synthetized by slow evaporation and its co-formers (A - ibuprofen; B - nicotinamide). Due to the results obtained by XRPD and Raman, the co-crystal synthetized by slow evaporation was used as a reference for full conversion of the initial substrates into 10 ACS Paragon Plus Environment

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the desirable product. This co-crystal was utilized as comparison material with the products obtained at the end of each reaction formed by the slurry conversion method. The Raman spectra was also used in the chemometric methods as an equality constraint on the spectra profile for one of the resulting components of the MCR-ALS. Synthesis and monitoring of the co-crystal in aqueous solution The reaction monitoring, as a process analytical tool, has as main advantages, the decrease in process time and less quantity of residuals. With the monitoring it is possible to design the experiments more efficiently, and understand the reaction mechanisms involved. In the case of co-crystallization reaction it is possible to observe a point where precipitation equilibrium is established, between the co-crystal of ibuprofen-nicotinamide and its co-formers. From this equilibrium process it is possible to design strategies to shift the equilibrium and thus increase the reaction yield. Usually, the crystallization reaction of ibuprofen-nicotinamide co-crystal utilize organic solvents, such as methanol and acetone8, 9. Under the green chemistry, the use of safer solvents is totally required. Water is an inert solvent from the environmental point of view, and is also used in wet compression process in tablet formulation. The water also provides advantages to the monitoring using Raman spectroscopy since this solvent presents low Raman scattering. Since water is used, it can be proven that non hydrate is formed during the process. Even though there is still a possibility of occurrence, the solvates will be less stable, thermodynamically, than the co-crystal; therefore the probability of forming its derivatives is very low. Reaction at room temperature

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The first reaction was performed at room temperature. 301 spectra were collected during 5 hours. At the end of the reaction a data matrix with 301 rows and 901 columns was obtained. The spectra were derived, normalized and smoothed by PCA. Figure 6 shows spectra at different reaction times obtained while monitoring, where a preliminary data analysis can be perform. The regions that show the most significant changes are at 640 cm-1, 800 cm-1 and between 1025 and 1050 cm-1. At the beginning of the reaction, only the ibuprofen spectrum (characteristic peak at 833 cm-1) and the nicotinamide in suspension (peak at 1041 cm-1) and solution (1033 cm-1) state can be observed. After 30 minutes, it is possible to note a peak at 797 cm-1, characteristic of the co-crystal, as well as an increase in peak at 1033 cm-1, however this peak can represent either the co-crystal or the nicotinamide in solution. With 2 hours of reaction all the cocrystal has been formed and the equilibrium has been achieved. At the end of the reaction, there are no significant changes in the intensity of the co-crystal peak. -1

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Figure 6. In-line spectra obtained at four different times at room temperature. Using only the co-crystal peak at 797 cm-1, it was possible to monitor its formation, using an univariate model, relating its intensity with a characteristic peak of ibuprofen or nicotinamide. In this case, many peaks presented in the co-crystal are also present in the spectra of its initial co-formers, making it difficult to choose the region to be 12 ACS Paragon Plus Environment

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analyzed. Hence, we preferred to use the MCR-ALS chemometric tool in order to perform a deconvolution of data. Figures 7 and 8 present the concentration (Ck) and spectral (ST) profile recovered by the model, respectively. The concentration profile shows that the co-crystal formation occurs rapidly. With only 70 minutes, the reaction had reached equilibrium. These data also corroborate with the thermodynamic stability of the co-crystal, because, even at room temperature, the ibuprofen and the nicotinamide, when in solution, tend to precipitate in a co-crystal form. The spectral profile is important only to identify each compound in the concentration profile, since an equality constraint was used in the spectra profile. The MCR-ALS model showed a good percentage of explained variance with 91.80 % of the data being explained by the model (R² = 0.92)

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Figure 7. Concentration profile of the reaction at room temperature.

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Ibuprofen Nicotinamide Co-crystal

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Figure 8. Integrated spectra used to realize the spectral deconvolution of the reaction at room temperature Reaction at 40 °C As a precipitation equilibrium could be observed between the co-crystal and its coformers, the reaction temperature was increased in order to shift both precipitation equilibrium and the solubility of the drugs in water. The reaction at 40 °C was carried out during 6 hours with the spectra acquired at intervals of 2 minutes, resulting in a matrix with 151 spectra and 901 columns. The spectra were normalized and smoothed by PCA. Figure 9 shows the spectra acquired during the monitoring at different times. At the beginning of the reaction, only the pure spectra of ibuprofen can be observed. With an hour of reaction, specific co-crystal peaks start to appear. At 2.5 hours, the ratio between the ibuprofen peak and the co-crystal peak is almost 1:1. At the end of the reaction (Time = 5 hours), the co-crystal peak shows a relative intensity greater than the ibuprofen and nicotinamide peaks.

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-1

1041 cm

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Figure 9.In-line spectra obtained at four different times at 40 °C. The concentration and spectral profile, recovered by the model, are shown in Figures 9 and 10, respectively. The concentration profile shows a quick conversion of the initial substrates into the co-crystal, with an hour of reaction, the equilibrium has been almost established. The co-crystal formation occurs much more slowly during the rest of the reaction. In the cooling stage, there is a large precipitation of nicotinamide, while part of ibuprofen is solubilized to form co-crystal. The reaction at 40 °C showed that with some heating it is possible to further the co-crystal formation. As in the room temperature reaction, the spectral profile only informs which concentration profile is of each species. The data exhibited a better fit than in the room temperature reaction. At 40 °C, almost 95 % of the data were explained by the model, R² = 0.94.

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1 Cooling Stage

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Figure 10.Concentration profile of the reaction at 40 °C. 0.6 Ibuprofen Nicotinamide Co-crystal

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0.4 0.3 0.2 0.1 0 -0.1 600

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Figure 11.Spectral profile used on the spectral deconvolution of the reaction at 40 °C. Reaction at room temperature The reaction at 60 °C occurred in a period of 6 hours, with an interval of two minutes between each spectrum. At the end of the reaction, all 151 spectra were organized in a matrix. They were derived, normalized and smoothed by PCA. After 35 minutes of 16 ACS Paragon Plus Environment

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reaction the solution was heated to 60 °C. This heating stage occurred during 3 hours, and was followed by a 105 minute cooling stage. Figure 12 shows five spectra acquired during the monitoring. At the beginning of the reaction, the spectrum is a mixture of ibuprofen and solid state nicotinamide. With an hour of reaction, the spectrum acquired has some peaks that resemble the co-crystal (797 cm-1 and 1033 cm-1) and others with the ibuprofen (CH2 and CH3 region in 900 – 1000 cm-1; peaks at 830 cm-1 and 743 cm-1). However, these peaks are shown wider than the usual spectral pattern of these compounds. In vibrational spectroscopy, wider bands can be found in amorphous structures or low crystallinity compounds, because slight changes in the energy of a same characteristic vibration could extend the peaks. On the other hand, high temperatures can distort some vibrational levels generating wider bands. At 2 hours, the peaks were sharper, and it was possible to observe the peaks of the cocrystal more clearly. Only the most intense peak of ibuprofen was still present in the spectrum, but with a low relativity intensity. With 2.5 hours, the reagents are totally solubilized, and the reaction media becomes translucent. The spectra acquired at this stage have a low intensity, very close to the baseline. Just the most intense peaks of each component are evident in these spectra. At the end of the monitoring, it is possible to observe a spectrum identical to the co-crystal spectrum.

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1041 cm-1 -1

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Figure 12. In-line spectra obtained at five different times at 60 °C. When the smoothing by PCA was carried out on the other reactions, only two principal components were given as significant, one correspondent to the ibuprofennicotinamide mixture spectrum and other to the co-crystal-ibuprofen-nicotinamide mixture spectrum. This occurs because the relativity concentration of ibuprofen and nicotinamide alter simultaneously. In the 60 °C reaction, the percentage of explained variance revealed that four principal components were significant. Hence, in the 60 °C reaction, the MCR-ALS was carried out with four components, and no equality constraint was used. As the initial spectral estimate, the function pure of MCR-ALS was used. This function retrieves the four most different spectra found in original data. The concentration and spectral profile were presented in Figures 13 and 14, respectively. The spectral profile shows four distinct spectra. One of the recovered spectrum is a mixture of ibuprofen and nicotinamide pure spectra; another is a mixture spectrum of ibuprofen and co-crystal; the third one is a recovered spectrum of instrumental noise; and at last, the pure spectrum of co-crystal.

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The recovered spectrum of the mixture of ibuprofen and co-crystal has wider bands, different from the sharp and resolved peaks that usually appear in the Raman spectrum. One possibility is that this recovered spectrum, that is also present in the original monitoring data (Figure 12, Time = 1h), can be related to a spectrum of the co-crystal center of nuclei that start to be formed near the ibuprofen crystals. This fact is reinforced by the concentration profile, recovered by the model. 1.6 Ibuprofen Ibuprofen+Co-crystal mixture Noise Co-crystal

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Cooling Stage

1.0 0.8 0.6 0.4 0.2 0 0

40

80

120

160 200 Time (min.)

240

280

320

360

Figure 13.Concentration profile of the reaction at 60 °C. At the beginning of the heating stage, only the noise and the mixture of co-crystal and ibuprofen spectra become evident in the reaction. After 80 minutes, the co-crystal spectrum starts to increase and the spectra of the other components decrease. Probably the co-crystal nuclei centers start to aggregate and form the co-crystals. At 130 minutes, the reaction becomes translucent. In this stage, the acquired spectra are related mostly by the instrumental noise. However it seems that there is a great contribution of the 19 ACS Paragon Plus Environment

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noise in this step, its relative intensity is very low. Therefore, from the whole data, it is only a small fraction. Another factor that corroborates to the great contribution of the noise in this step is that Raman scattering occurs very well in solids and suspension systems, when there is a huge quantity of molecules to scatter the laser. In translucent systems, the Raman scattering is very low, and the noise is more evident. In the cooling stage, the crystals precipitate in the form of ibuprofen-nicotinamide co-crystal, with a total conversion. 0.45 Ibuprofen Ibuprofen+Co-crystal mixture Noise Co-crystal

0.4 0.35 0.3 Relative Intesity (counts)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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0.25 0.2 0.15 0.1 0.05 0 -0.05

600

650

700

750

800 850 900 Raman Shift (cm-1)

950

1000

1050

1100

Figure 14. Spectral profile of the reaction at 60 °C. As no equality constraint has been used, the data fit for the 60 °C reaction presents a better fit compared to other reactions. Practically all the data has been explained by the model with R² = 0.999997 and lack of fit = 0.18042 %.

Conclusion

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The co-crystallization reaction of ibuprofen-nicotinamide was conducted using a green synthesis and environmental correctness. The reactions were carried out without any organic solvent and using an in-line monitoring by Raman spectroscopy. The in-line monitoring and the chemometrics tools like PCA and MCR-ALS allowed to get a higher quantity of information about the reaction, such as identification of the the end point of the reaction, the understanding of drug crystallization mechanisms and a more efficient design of experimental proceedings It was possible to recognize the precipitation equilibrium between the co-formers and the final product. Thus, it was possible to perform experiments with the objective to move the chemical equilibrium involved. The reaction at 60 °C allowed the total conversion of the initial reagents to form the co-crystal. Author information Corresponding Author E-mail: [email protected] or [email protected] Funding Sources CAPES (Coordenação de Aperfeiçoamento de Pessoal Nível Superior) and FAPESP (Fundação de Apoio à Pesquisa do Estado de São Paulo) Proc. 2010/16520-5. Bibliography (1)

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phases:

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carbamazepine. Cryst Growth Des 2003, 3, (6), 909-919. (2)

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Choudhury, A. R.; Desiraju, G. R.; Dikundwar, A. G.; Dubey, R.; Duggirala, N.;

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Ghogale, P. P.; Ghosh, S.; Goswami, P. K.; Goud, N. R.; Jetti, R. R. K. R.; Karpinski, P.; Kaushik, P.; Kumar, D.; Kumar, V.; Moulton, B.; Mukherjee, A.; Mukherjee, G.; Myerson, A. S.; Puri, V.; Ramanan, A.; Rajamannar, T.; Reddy, C. M.; RodriguezHornedo, N.; Rogers, R. D.; Row, T. N. G.; Sanphui, P.; Shan, N.; Shete, G.; Singh, A.; Sun, C. C.; Swift, J. A.; Thaimattam, R.; Thakur, T. S.; Kumar Thaper, R.; Thomas, S. P.; Tothadi, S.; Vangala, V. R.; Variankaval, N.; Vishweshwar, P.; Weyna, D. R.; Zaworotko, M. J., Polymorphs, Salts, and Cocrystals: What’s in a Name? Cryst Growth Des 2012, 12, (5), 2147-2152. (3)

Monissette, S. L.; Almarsson, O.; Peterson, M. L.; Remenar, J. F.; Read, M. J.;

Lemmo, A. V.; Ellis, S.; Cima, M. J.; Gardner, C. R., High-throughput crystallization: polymorphs, salts, co-crystals and solvates of phan-naceutical solids. Adv Drug Deliver Rev 2004, 56, (3), 275-300. (4)

Braga, D.; Grepioni, F.; Maini, L., The growing world of crystal forms.

Chemical Communications 2010, 46, (34), 6232-6242. (5)

Friscic, T.; Jones, W., Benefits of cocrystallisation in pharmaceutical materials

science: an update. J Pharm Pharmacol 2010, 62, (11), 1547-1559. (6)

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analysis of pharmaceutical polymorphs. J Pharmaceut Biomed 2011, 55, (4), 618-644. (7)

Yazdanian, M.; Briggs, K.; Jankovsky, C.; Hawi, A., The "high solubility"

definition of the current FDA Guidance on Biopharmaceutical Classification System may be too strict for acidic drugs. Pharm Res 2004, 21, (2), 293-299. (8)

Alshahateet, S. F., Synthesis and Supramolecularity of Hydrogen-Bonded

Cocrystals of Pharmaceutical Model Rac-Ibuprofen with Pyridine Derivatives. Mol Cryst Liq Cryst 2010, 533, 152-161.

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(9)

Friscic, T.; Jones, W., Cocrystal architecture and properties: design and building

of chiral and racemic structures by solid-solid reactions. Faraday Discuss 2007, 136, 167-178. (10)

Chen, S.; Xi, H. M.; Henry, R. F.; Marsden, I.; Zhang, G. G. Z., Chiral co-

crystal solid solution: structures, melting point phase diagram, and chiral enrichment of (ibuprofen)(2)(4,4-dipyridyl). Crystengcomm 2010, 12, (5), 1485-1493. (11)

Berry, D. J.; Seaton, C. C.; Clegg, W.; Harrington, R. W.; Coles, S. J.; Horton,

P. N.; Hursthouse, M. B.; Storey, R.; Jones, W.; Friscic, T.; Blagden, N., Applying hotstage microscopy to co-crystal screening: A study of nicotinamide with seven active pharmaceutical ingredients. Cryst Growth Des 2008, 8, (5), 1697-1712. (12)

Bag, P. P.; Patni, M.; Malla Reddy, C., A kinetically controlled crystallization

process for identifying new co-crystal forms: fast evaporation of solvent from solutions to dryness. Crystengcomm 2011, 13, (19), 5650-5652. (13)

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Improving the Mechanical Properties, Dissolution Performance, and Hygroscopicity of Ibuprofen and Flurbiprofen by Cocrystallization with Nicotinamide. Pharm Res 2012, 29, (7), 1854-1865. (14)

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continuous

cocrystallization (SFCC) using near infrared spectroscopy as a PAT tool. Int J Pharmaceut 2012, 426, (1-2), 15-20.

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For Table of Contents Use Only

Green Synthesis of Ibuprofen-Nicotinamide Co-crystals and In-line evaluation by Raman Spectroscopy

Frederico L. F. Soares*, Renato L. Carneiro

Synopsis This article reports a green synthesis of ibuprofen-nicotinamide co-crystal in aqueous media and its monitoring by Raman spectroscopy and chemometrics methods, such as MCR-ALS and PCA as PAT tools.

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CH3

O

OH

N

CH3

NH2

O H3C

1 Ibuprofen Nicotinamide Co-crystal

0.9 0.8

MCR

Relativity Intensity

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0.3 0.25

C

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Ibuprofen Nicotinamide Co-crystal

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1 Cooling Stage

Heating Stage

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Ibuprofen Ibuprofen+Co-crystal mixture Noise Co-crystal Cooling Stage

Heating Stage

Relativity Intensity

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CH3

O

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N

CH3

NH2

O H3C

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