Ibuprofen lysinate

The stable anhydrous ibuprofen lysinate can be produced by the combination of lysine in water and ibuprofen in ethanol at room temperature such that the final water level in the solvent mixture is below 5 weight %. If the weight % of water is greater than 5%, a monohydrate of ibuprofen lysinate is obtained. The monohydrate converts to anhydrous ibuprofen lysinate if water is flushed out by the anhydrous ethanol. 

A compound, a class HI antiarrhythmic agent, which is a hydrochloride salt and a combination of a substituted heteroatomic tricyclic system with a substituted tetrahydronaphthyl system, provides an interesting example that merges hydration with polymorphism. The compound exists as a soUd at room temperature with a melting-decomposition point in excess of 200 C. 

When the compound is isolated from certain organic solvents, particularly ordinary alcohols, the corresponding solvate is obtained. When the solvent is removed by drying, the resulting solid is hygroscopic and adsorbs water from the atmosphere to give stoichiometric hydrates. With other organic 

Three hydrates of the compound, designated Types A, B, and D, have been found and characterized. The XRPD patterns and the TG curves are represented in Figs. 3-11 and 3-12, respectively. 

Selecting and producing the solid phase of this compound for pharmaceutical applications indicates how complex these situations can become. The organic solvates, in general, are ruled out based 

---

C6H14N2O2 56-87-1) see Eptifibatide Gusperimus trihydrochloride Ibuprofen lysinate Lisinopril Lymecycline... 

An example of monotropic behavior consists of the system formed by anhydrous ibuprofen lysinate [41,42], Figure 4.12 shows the DSC thermogram of this compound over the temperature range of 20-200°C, where two different endothermic transitions were noted for the substance (one at 63.7°C and the other at 180.1°C). A second cyclical DSC scan from 25 to 75°C demonstrated that the 64°C endotherm, generated on heating, had a complementary 62°C exotherm, formed on cooling (see Fig. 4.13). The superimposable character of the traces in the thermograms demonstrates that both these processes were reversible, and indicates that the observed transition is associated with an enantiotropic phase interconversion [41]. X-ray powder (XRPD) diffraction patterns acquired at room temperature, 70°C, and... 

Fig. 4.12. DSC thermogram of non-solvated ibuprofen lysinate, illustrating the enantiotropic conversion of the metastable phase to the more stable phase (64°C endotherm) and subsequent melting of the stable form (181°C endotherm).

Fig. 4.13. Demonstration of the enantiotropic reversibility associated with the phase conversion between the non-solvated polymorphs of ibuprofen lysinate.

Taking advantage of the ready availability of racemic ibuprofen, the resolution approach for production of (S)-(+)-ibuprofen becomes an attractive alternative. Merck s resolution process involves the formation of a diastereomeric salt of ibuprofen with (S)-lysine, an inexpensive and readily available natural amino acid.45 The racemic ibuprofen is mixed with 1.0 equivalent of (5)-lysine in aqueous ethanol. The slurry is agitated to allow full dissolution. The supernatant, which is a supersaturated solution of ibuprofen-lysine salt, is separated from the solid and seeded with (.S )-ibuprofcn-(.S )-lysine to induce crystallization. The precipitated solid is collected by filtration, and the mother liquor is recycled to the slurry of racemic ibuprofen and (S)-lysine. This process is continued until essentially all (S)-ibuprofen in the original slurry is recovered, resulting in the... 

For therapeutic purposes, a similar frequently used group of drug compounds is the non-steroidal antiinflammatory drugs (NSAIDs). One of the best known representatives of the aryl acetic acid derivatives in diclofenac and that of aryl propionic acid derivatives ibuprofen. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions, these amphiphilic organic acids may form lyotropic mesophases with water at even room or body temperature e.g., diclofenac diethylamine or ibuprofen lysinate. Furthermore, some anhy-drates of NSAID, e.g., fenoprofen calcium,exhibit thermotropic mesomorphism after thermal dehydration of the crystalline salt. 

Ibuprofen lysine is more rapidly absorbed than ibuprofen free acid, but the comparative tolerability of the two formulations is not known (SEDA-20, 93). 

A high degree of control can also be achieved in continuously stirred tank crystallizers. Temperature differences between feed and crystallizer can be regulated as necessary. The seed is the product and will normally be present at the slurry concentration as determined by the feed rate, concentration, and solubility differences achieved. However, in cases in which this amount of seed is not sufficient, cross-flow filtration on the discharge of the crys-tallizer(s) can be used to increase the slurry density. See Example 7-4 for a discussion of the resolution of ibuprofen lysinate. 

Metastability and induction time can play an interesting role in the kinetic resolution of optical isomers, such as of resolution of ibuprofen lysinate (see Example 7.4). On the one hand in order to maintain the optical purity of the desired isomer, it is necessary to keep the (undesired) isomer in its supersaturated state for the entire crystallization period. If the undesired isomer crystallizes out from the solution, the optical purity of the desired isomer will decrease. On the other hand, it is important to release the supersaturation of the desired isomer, which starts at the same initial level of supersaturation as the undesirable isomer. These are two conflicting requirements. To overcome this dilemma, it is critical to maintain a large amount of seed bed of the desired isomer to accelerate the release of super-saturation of the desired isomer, whereas the undesired isomer remains supersaturated. As mentioned, a detailed description of the resolution process of optical isomers is given in Example 7-4. 

Figure 2-18 Solubility of the anhydrous solid and the monohydrate of ibuprofen lysinate. When the water level is above 5%, the monohydrale is more stable. When the water level is below 5%, the anhydrous solid is more stable.

Solvated crystals are also common in the chemical and pharmaceutical industries. Figure 2-18 shows the room temperamre solubility curve of ibuprofen-lysinate as a function of water content in ethanol. As shown in the figure, the crossover point between anhydrous solid and monohydrate is < 5% water. At room temperamre, ibuprofen-lysinate remains anhydrous when the water content is below 5% and transforms into monohydrate when the water content is above 5%. In this example, solvate and anhydrous materials also have different crystal habits, as shown in Fig. 2-19. 

Figure 2-19 Crystals of the anhydrous solid and the monohydrate crystals of ibuprofen lysinate.

Anhydrous ibuprofen lysinate, an analgesic agent, provides another example of enantiotropic polymorphs. Figure 3-9 exhibits a representative DSC curve for anhydrous ibuprofen lysinate. The curve has features that are similar to those of the DSC curve for Form I of finasteride. However, the XRPD pattern after heating to a temperature above that of the minor endotherm for anhydrous ibuprofen lysinate and cooling back to room temperature remains unchanged, in contrast to the finasteride... 

Figure 3-10 Cyclic DSC for ibuprofen lysinate (heat/coal cycle).

Santi, R, Nicoli, S., Colombo, G., Bettini, R., Artusi, M., Rimondi, S. et al. (2003) Post iontophoresis transport of ibuprofen lysine across rabbit ear skin . Int. J. Pharm. 266,... 

Ibuprofen lysinate 2017 N-coco acyl derivs, chlorides, ... 

Wamecke J, Pentz R, Siegers C-P. Effects of smoking and contraceptives on the pharmacokinetics and pharmacodynamics of S(+)-ibuprofen lysinate in humans. Naunyn Schmiedebergs Arch Pharmacol (1996) 354 (Suppl 1), R33. 

In another study, preterm infants were given amikacin 20 mg/kg every 36 hours (gestational age less than 30 weeks) or every 24 hours (gestational age 30 to 31 weeks) with either ibuprofen lysine 10 mg/kg within 6 hours of birth, then a further 5 mg/kg dose 24 and 48 hours later, or placebo. The half-life of amikacin was increased from 12.4 to 16.4 hours and its clearance was reduced by 40% in infants who also received intravenous ibuprofen lysine. Reductions in amikacin clearance, independent of gestational age were found by the same authors in another study in which preterm infants with gestational ages of between 24 and 34 weeks were given amikacin and ibuprofen. ... 

Another interesting example of combining diastereomeric salt formation and racemization was reported by Bhattacharya." In this work, selective crystallization of ibuprofen/lysinate from 1 mol of (/ ,5)-(racemic) ibuprofen and <0.5 mol of (5)-lysine in aqueous ethanol affords either (S)-(- -)-ibuprofen/(5)-lysinate or (/ )-ibuprofen/(5)-lysinate (in preponderance) depending on the crystallization conditions. Then, the unwanted enantiomeric ibuprofen could be recovered from the mother liquor and racemized by a simple, relatively waste-free thermal process. The combination of the thermal racemization process and the selective crystallization technology provides an efficient and environmentally friendly means to prepare (S)-(- -)-ibuprofen lysinate in an overall essentially quantitative yield (Figure 56.8). 

---