Predicting outcome in ex-premature infants supported with extracorporeal membrane oxygenation for acute hypoxic respiratory failure.

OBJECTIVE: To identify predictors of outcome in ex-premature infants supported with extracorporeal membrane oxygenation (ECMO) for acute hypoxic respiratory failure. METHODS: Retrospective review of ex-premature infants with acquired acute hypoxic respiratory failure requiring ECMO support in the United Kingdom from 1992 to 2001. Review of follow up questionnaires completed by general practitioners and local paediatricians. RESULTS: Sixty four ex-premature infants (5-10 each year) received ECMO support, despite increased use of advanced conventional treatments over the decade. The most common infective agent was respiratory syncytial virus (85% of cases). Median birth gestation was 29 weeks and median corrected age at the time of ECMO support was 42 weeks. Median ECMO support duration was relatively long, at 229 hours. Survival to hospital discharge and to 6 months was 80%, remaining similar throughout the period of review. At follow up, 60% had long term neurodisability and 79% had chronic pulmonary problems. Of pre-ECMO factors, baseline oxygen dependence, younger age, and inpatient status were associated with non-survival (p < or = 0.05). Of ECMO related factors, patient complications were independently associated with adverse neurodevelopmental outcome and death (p < 0.01). CONCLUSIONS: Survival rates for ex-premature infants after ECMO support are favourable, but patients suffer a high burden of morbidity during intensive care and over the long term. At the time of ECMO referral, baseline oxygen dependence is the most important predictor of death, but no combination of the factors considered was associated with a mortality that would preclude ECMO support.

Molecular modeling study of chiral drug crystals: lattice energy calculations.

The lattice energies of a number of chiral drugs with known crystal structures were calculated using Dreiding II force field. The lattice energies, including van der Waals, Coulombic, and hydrogen-bonding energies, of homochiral and racemic crystals of some ephedrine derivatives and of several other chiral drugs, are compared. The calculated energies are correlated with experimental data to probe the underlying intermolecular forces responsible for the formation of racemic species, racemic conglomerates, or racemic compounds, termed chiral discrimination. Comparison of the calculated energies among ephedrine derivatives reveals that a greater Coulombic energy corresponds to a higher melting temperature, while a greater van der Waals energy corresponds to a larger enthalpy of fusion. For seven pairs of homochiral and racemic compounds, correlation of the differences between the two forms in the calculated energies and experimental enthalpy of fusion suggests that the van der Waals interactions play a key role in the chiral discrimination in the crystalline state. For salts of the chiral drugs, the counter ions diminish chiral discrimination by increasing the Coulombic interactions. This result may explain why salt forms favor the formation of racemic conglomerates, thereby facilitating the resolution of racemates.

Polymorph screening: influence of solvents on the rate of solvent-mediated polymorphic transformation.

Solvent-mediated polymorphic transformation is an efficient technique to obtain the most stable polymorph. The rate of solvent-mediated polymorphic transformation of sulfamerazine at 24 degrees C in various solvents and solvent mixtures is controlled by the nucleation rate of the more stable Form II. The transformation rate is generally higher in the solvent giving a higher solubility and is low in the solvent giving a low solubility (8 mmol/L). In these solvents, because of a high interfacial energy, the metastable zone may be wider than the solubility difference between two polymorphs, such that the critical free energy barrier for nucleation cannot be overcome. In addition to the solubility, the strength of the solvent-solute interactions is also important in determining the transformation rate. For sulfamerazine, the transformation rate is lower in the solvent with a stronger hydrogen bond acceptor propensity. Because solubility is higher in the solvent with stronger hydrogen bond acceptor propensity, the balance of solubility and strength of hydrogen bonding interactions between the solute and solvent molecules determines the polymorphic transformation rate. Degree of agitation and temperature also change the polymorphic transformation rate by influencing the crystallization kinetics of the more stable polymorph.

Hydrogen bonding in sulfonamides.

The hydrogen-bond connectivity in 39 sulfonamide crystal structures has been deciphered and described using graph set notation. The hydrogen-bond connectivity observed is used to gain information on hydrogen-bond preferences of specific donor and acceptor atoms of related sulfonamide molecules. The amido protons show a greater preference for hydrogen bonding to amidine nitrogens and cocrystal guests, whereas the amino protons show a greater preference for hydrogen bonding to sulfonyl oxygens, forming the only dominant hydrogen-bond pattern, a chain with an eight atom repeat unit. Preferential hydrogen bonding between the amidine group and the guest carboxyl group was observed in five cocrystal structures of sulfamethazine. Sulfamoxole displays a conformation and a hydrogen-bond motif not seen in any other structures. Sulfamerazine and sulfamethazine, differing by a methyl group, show no similarity in hydrogen-bond pattern, whereas sulfamethoxydiazine and sulfamethoxymethazine, which have sterically similar but chemically different heterocycles, show a striking similarity in hydrogen-bond pattern. Sulfamethoxydiazine, sulfamethoxymethazine, and sulfamethoxazole also show a large variation in hydrogen-bond pattern between polymorphs. Studies such as this, by revealing details of hydrogen-bonding patterns in closely related organic crystal structures, can potentially provide predictive capability among the crystal structures of pharmaceutical solids.

Estimating the relative stability of polymorphs and hydrates from heats of solution and solubility data.

The transition temperature, T(t), of polymorphs is estimated from both their heats of solution and solubilities (or intrinsic dissolution rates) determined at any one temperature (e.g., ambient). At a given temperature, T, the enthalpy difference, DeltaH, between polymorphs, I and II, is equal to the difference between their heats of solution, whereas the free energy difference, DeltaG, can be estimated by the equation, DeltaG = -RTln (c(I)/c(II)) or DeltaG = -RTln (J(I)/J(II)), where c is the solubility and J is the intrinsic dissolution rate. The entropy difference, DeltaS, is evaluated as (DeltaH - DeltaG)/T. Because the heat capacity difference,DeltaC(p) between polymorphs is small enough to be neglected, the transition temperature may be estimated by the equation, T(t) = DeltaH/DeltaS. The thermodynamic stability relationships of the polymorphs (i.e., whether they are enantiotropes or monotropes) are predicted from the value of T(t) and the melting temperature. The T(t) values for auranofin, carbamazepine, chloramphenicol palmitate, cyclopenthiazide, gepirone hydrochloride, lamivudine, MK571, premafloxacin, sulfamerazine, sulfamethoxazole, sulfathiazole, and urapidil, were calculated from reported values of the heats of solution and solubilities (or dissolution rates). The stability relationships deduced from the calculated values of T(t) are in good agreement with those reported using other methods, such as differential scanning calorimetry and interpretation of melting data.

Influence of crystal structure on the tableting properties of sulfamerazine polymorphs.

PURPOSE: To understand the influence of polymorphic structure on the tableting properties of sulfamerazine. METHODS: Bulk powders of sulfamerazine polymorph I and of two batches. II(A) and II(B) of different particle size, of polymorph II were crystallized. The powders were compressed to form tablets whose porosity and tensile strength were measured. The relationships between tensile strength, porosity and compaction pressure were analyzed by the method developed by Joiris. E., et al. Pharm. Res. 15:1122-1130 (1998). RESULTS: The sensitivity of tensile strength to compaction pressure, known as the tabletability, follows the order. I >> II(A) > II(B) and the porosity at the same compaction pressure, which measures the compressibility, follows the order, I << II(A) < II(B). Therefore. the superior tabletability of I over II(A) or II(B) is attributed to its greater compressibility. Molecular simulation reveals slip planes in crystals of I but not in II. Slip planes provide I crystals greater plasticity and therefore greater compressibility and tabletability. Larger crystal size of II(B) than of II(A) leads to fewer contact points between crystals in the tablets and results in a slightly lower tabletability. CONCLUSIONS: Slip planes confer greater plasticity to crystals of I than II and therefore greater tabletability.

Compaction properties of L-lysine salts.

PURPOSE: To examine the effects of salt form, i.e., different anions with a common cation (L-lysinium), on compaction properties and to identify the factors that determine the tensile strength of tablets. METHODS: L-Lysine salts with the following anions were compressed at various pressures: acetate, monochloride, dichloride, L-aspartate, L-glutamate (dihydrate), and L-lysine (zwitterionic monohydrate). The yield strength of each salt was evaluated from the "out-of-die" Heckel plot. RESULTS: At low compaction pressures, the tensile strength of the compacts increases linearly with increasing compaction pressure. Simultaneously. the compact tensile strength decreases exponentially with increasing yield strength of the salt. However, at high compaction pressures, the compact tensile strength is determined by the interparticulate bonding strength and not by the yield strength. The compact tensile strength, extrapolated to zero porosity, increases linearly with increasing melting temperature of the salts. CONCLUSIONS: The counterion affects the tableting properties of L-lysine salts. The tensile strength is controlled by both the yield strength and the interparticulate interaction strength with the former predominant at low compaction pressures and the latter predominant at high compaction pressures. The melting temperature of each L-lysine salt is a good indicator of the tensile strength of its compacts at zero porosity.

Influence of elastic deformation of particles on Heckel analysis.

The Heckel equation is one of the most useful equations for describing the compaction properties of pharmaceutical powders. Important material properties (e.g., yield strength) of powders can be derived using Heckel analysis. Two types of Heckel analysis are in common use. One is the "out-of-die," or "zero-pressure" method, the other is the "in-die" or "at-pressure" method. Because particles undergo elastic deformation under pressure, which tends to lower the porosity of the powder bed, the "out-of-die" method describes powder consolidation and compaction more accurately than the "in-die" method. However, "in-die" Heckel analysis has been widely used because of the speed and ease of data collection. Using L-lysine monohydrochloride dihydrate as a model compound, this work analyzes quantitatively the effects of elastic deformation on the calculation of porosity of a tablet, and therefore on the Heckel analysis. The effects of a small change in porosity, epsilon, on Heckel analysis are presented mathematically. It is found that a decrease in porosity of 0.001, when the porosity is lower than 0.05, causes a significant increase in the value of -ln epsilon. Therefore, data at epsilon < 0.05 should be interpreted with caution when using Heckel analysis. Elastic deformation causes positive deviations in the Heckel plot, and therefore leads to a yield strength that is lower than the true value. The lower the elastic modulus of the powder, the greater is the deviation from the true value. Therefore, the "in-die" method gives values of yield strength that are significantly lower than the true values for most pharmaceutical powders.

Influence of crystal shape on the tableting performance of L-lysine monohydrochloride dihydrate.

The purpose of this study is to understand the influence of crystal shape on the tableting performance of L-lysine monohydrochloride (LMH) dihydrate, using the method of data analysis developed by Joiris E et al. 1998. Pharm Res 15:1122-1130. Phase-pure crystals of LMH dihydrate, prism-shaped (S) and plate-shaped (T), were prepared by adjusting the composition of the crystallization solvent. At the same compaction pressure, T always gives stronger tablets than S, (i.e.; the tabletability of T is greater). The porosity of tablets from T crystals is always greater than that of S crystals when compressed at the same pressure, (i.e.; the compressibility of T is lower). The tensile strength of T tablets, at the same porosity, is greater than that of S tablets, (i.e.; the compactibility of T is greater). Therefore, the greater tabletability of T is a result of its better compactibility that overcomes the negative effects by its lower compressibility. The greater compactibility of T is related to favorable orientation of the slip planes in the tablet, corresponding to greater plasticity under load. The yield strengths of T and S crystals are essentially the same (20 MPa). Therefore, the crystal shape influences the tableting performance but does not, in principle, affect the yield strength of LMH dihydrate.

Crystalline solids.

Many drugs exist in the crystalline solid state due to reasons of stability and ease of handling during the various stages of drug development. Crystalline solids can exist in the form of polymorphs, solvates or hydrates. Phase transitions such as polymorph interconversion, desolvation of solvate, formation of hydrate and conversion of crystalline to amorphous form may occur during various pharmaceutical processes, which may alter the dissolution rate and transport characteristics of the drug. Hence it is desirable to choose the most suitable and stable form of the drug in the initial stages of drug development. The current focus of research in the solid-state area is to understand the origins of polymorphism at the molecular level, and to predict and prepare the most stable polymorph of a drug. The recent advances in computational tools allow the prediction of possible polymorphs of the drug from its molecular structure. Sensitive analytical methods are being developed to understand the nature of polymorphism and to characterize the various crystalline forms of a drug in its dosage form. The aim of this review is to emphasize the recent advances made in the area of prediction and characterization of polymorphs and solvates, to address the current challenges faced by pharmaceutical scientists and to anticipate future developments.

Effects of initial particle size on the tableting properties of L-lysine monohydrochloride dihydrate powder.

L-lysine monohydrochloride (LMH) dihydrate was crystallized and the resulting powder was sieved to obtain various size fractions. The influence of other factors, such as crystallinity and crystal shape, was minimized by using the same batch of crystals. Compression of smaller particles at low compaction pressures resulted in tablets of greater porosity. The differences in porosity decreased with increasing compaction pressure. At the same compaction pressure, smaller particles formed tablets of greater tensile strength. However, fragmentation of the larger particles tended to equalize the particle size and reduce its influence. The differences were reduced for particles larger than 710 microm. For crystals of all size fractions, tensile strength increased with increasing compaction pressure. The tensile strength increased more rapidly for smaller crystals. Tensile strength decreased exponentially with increasing porosity for all fractions. The dependence of tensile strength on porosity is explained in term of tablet structure. Yield strength, calculated from 'out-of-die' Heckel analysis, increased with increasing particle size.

Dehydration behavior of nedocromil magnesium pentahydrate.

The dehydration of nedocromil magnesium (NM) pentahydrate proceeds in two steps, corresponding to the loss of four water molecules in the first step and one water molecule in the second step. The effects of temperature, particle size, sample weight, water vapor pressure and dehydration-rehydration cycle on both the kinetics and activation energy of the dehydration of NM pentahydrate were studied using isothermal TGA and temperature-ramp DSC analyzed by Kissinger's method. The dehydration kinetics for both steps are best described by the Avrami-Erofeev equations, suggesting a nucleation-controlled mechanism. The high activation energy for the second dehydration step indicates that the last water molecule, which is bonded both to a magnesium ion and to a carboxylate oxygen atom, is more 'tightly bound'. The activation energy decreased with increasing sample weight and decreasing particle size. The dehydration rate increased with decreasing water vapor pressure and with repetition of the dehydration-hydration cycle. Dynamic and isothermal PXRD, and 13C solid-state NMR were employed to provide an insight into the dehydration mechanism and the nature of solid-state phase transformation during the dehydration. Molecular modeling with Cerius(2) was used to visualize the crystal structure and to construct the molecular packing diagram. A correlation was noted between the dehydration behavior and the bonding environment of the water molecules in the crystal structure.

Effects of crystallization in the presence of the diastereomer on the crystal properties of (SS)-(+)-pseudoephedrine hydrochloride.

The formation and separation of diastereomers is widely used to resolve enantiomers. However, during crystallization of a chiral compound from a solution containing its diastereomer, the diastereomer may be incorporated as an impurity into the host crystal lattice, leading to changes in the thermodynamic properties and intrinsic dissolution rate of the host crystals. This hypothesis was tested by growing crystals of (SS)-(+)-pseudoephedrine hydrochloride (+PC) from aqueous solution containing various amounts of (RS)-(-)-ephedrine hydrochloride (-EC). Although the melting phase diagram of these two solid compounds, determined by differential scanning calorimetry (DSC), shows eutectic behavior, 0.034-2.4 mol% of -EC was incorporated into the crystal lattice of +PC during crystallization to form terminal solid solutions with a segregation coefficient of 0.31. In a single batch, the larger crystals contain more incorporated impurities than smaller crystals. The enthalpy and entropy of fusion measured by DSC decrease with increasing incorporation of the guest molecules into the host, indicating increases in the enthalpy and entropy of the solid. The disruption index, which indicates the disruptive effect of guest molecules in the host crystal lattice, is 60 at < or = 0.084 mol% of -EC in +PC crystals, but is only 5 at higher levels of -EC. The greater disruptive effect at lower levels of impurity incorporation may be explained by the formation of substitutional solid solutions in which the impurity molecules disrupt the hydrogen bonding network in the host crystals, whereas additional incorporated impurity may be adsorbed onto the surfaces of the mosaic blocks with reduced effect on the crystal lattice. The average intrinsic dissolution rate of impure crystals in 2-propanol is 15.8% lower than that of pure host crystals, suggesting the formation of stable solid solutions.

Nuclear magnetic resonance and infrared spectroscopic analysis of nedocromil hydrates.

PURPOSE: Nedocromil sodium (NS), which is used in the treatment of reversible obstructive airway diseases, such as asthma, has been found to exist in the following solid phases: the heptahemihydrate, the trihydrate, a monohydrate, an amorphous phase, which contains variable amounts of water, and a recently discovered methanol + water (MW) solvate. Our aim was to apply 13C solid-state nuclear magnetic resonance (NMR) spectroscopy and solid-state Fourier transform infrared (FTIR) spectroscopy to the study of specific interactions in the various solid forms of NS. METHODS: The 13C solid-state NMR and FTIR spectra of the various solid forms of NS were obtained and were related to the crystal structures of NS, the conformations of the nedocromil anion, and the interactions of the water molecules in these crystals. RESULTS: The 13C solid-state NMR spectrum is sensitive to the conformation of the nedocromil anion, while the solid-state FTIR spectrum is sensitive to interactions of water molecules in the solid state. In NS monohydrate, for which the crystal structure has not yet been solved, and in the amorphous phase, the information about the conformations of the nedocromil anion and the interactions of the water molecules are deduced from the 13C solid-state NMR spectra and solid-state FTIR spectra, respectively. CONCLUSIONS: 13C solid-state NMR spectroscopy and solid-state FTIR spectroscopy are shown to be powerful complementary tools for probing the chemical environment of molecules in the solid state, specifically the conformation of the nedocromil anion and the interactions of water-molecules, respectively.

In situ dehydration of carbamazepine dihydrate: a novel technique to prepare amorphous anhydrous carbamazepine.

The purposes of this project were to prepare amorphous carbamazepine by dehydration of crystalline carbamazepine dihydrate, and to study the kinetics of crystallization of the prepared amorphous phase. Amorphous carbamazepine was formed and characterized in situ in the sample chamber of a differential scanning calorimeter (DSC), a thermogravimetric analyzer (TGA), and a variable temperature x-ray powder diffractometer (VTXRD). It has a glass transition temperature of 56 degrees C and it is a relatively strong glass with a strength parameter of 37. The kinetics of its crystallization were followed by isothermal XRD, under a controlled water vapor pressure of 23 Torr. The crystallization kinetics are best described by the three-dimensional nuclear growth model with rate constants of 0.014, 0.021, and 0.032 min-1 at 45, 50, and 55 degrees C, respectively. When the Arrhenius equation was used, the activation energy of crystallization was calculated to be 74 kJ/mol in the presence of water vapor (23 Torr). On the basis of the Kissinger plot, the activation energy of crystallization in the absence of water vapor (0 Torr water vapor pressure) was determined to be 157 kJ/mol. Dehydration of the dihydrate is a novel method to prepare amorphous carbamazepine; in comparison with other methods, it is a relatively gentle and effective technique.

Influence of crystal habit on the surface free energy and interparticulate bonding of L-lysine monohydrochloride dihydrate.

The objective of the present study was to apply a technique to measure the surface energy of crystalline powders without changing the surface properties by compaction, and to relate such measurements to crystal habit and orientation. The surface free energy of uncompacted L-lysine monohydrochloride dihydrate (LH), determined using a modified sessile-drop method, reflected a combined value for the various faces, and was influenced by the relative size of the faces and the orientation of the crystals. The surface free energy values obtained from contact angle measurements were within the possible range calculated from the crystal structure. Discrepancies between the theoretical estimates of interparticulate cohesive strengths and those measured from the tensile strength of powder compacts were used to estimate the flaw sizes (or gaps between the particles) that act as stress concentrators and reduce the tensile strength of the compacts. The flaw sizes indicate packing and compressibility of the various crystal habits. In the absence of compressive load, compacts made out of the equidimensional crystals have the larger flaw sizes (wider cracks or wider gaps between the particles). At higher compaction pressures, the compacts from long rod-shaped crystals have longer crack lengths. The weakness of the compacts made from the long rods at the higher compaction pressures may be because of the longer crack length along the interparticulate boundary, which may result in a higher stress intensity at the crack tip and increased fracture propensity.

Bilirubin UDP-glucuronosyltransferase 1A1 gene polymorphisms: susceptibility to oxidative damage and cancer?

The UDP-glucuronosyltransferase 1A1 (UGT1A1) gene product catalyzes the glucuronidation of serum bilirubin as part of normal heme catabolism. Recently, TA repeat polymorphisms containing five, six, seven, and eight TA dinucleotides in a putative TATA box in the promoter region of the UGT1A1 gene have been described. TA repeat number modulates UGT1A1 transcriptional activity and the quantity of enzyme available to conjugate serum bilirubin. Serum bilirubin is a known antioxidant, and low serum bilirubin has been associated with increased risk for coronary artery disease and inhibition of reactive oxygen species (ROS)-induced damage to erythrocytes in vitro. We hypothesize that the UGT1A1 TA repeats or other functional polymorphisms resulting in lower serum bilirubin levels may be predictive of genetic susceptibility to oxidative damage and cancer. Exposure-related or endogenous production of ROS may impact the integrity of cellular macromolecules and infrastructure, lead to DNA base changes or chromosomal aberrations, and induce toxicity or apoptosis. ROS damage to lipoproteins may be a factor in formation of atherogenic plaques in coronary heart disease. Thus, cellular oxidative stress could contribute to tumorigenesis through mutagenic or epigenetic pathways, and higher serum bilirubin levels should inhibit this process. No definitive studies have been performed, but in a small prospective study of colon cancer, serum bilirubin levels were observed to be lower in these cases. Another study has suggested a link between UGT1A1 alleles, estrogen metabolism, and risk in breast cancer. Epidemiologic studies examining variation in ROS metabolism, ROS damage, bilirubin, and cancer risk will demonstrate the value of this hypothesis.

Solid-state behavior of cromolyn sodium hydrates.

Cromolyn sodium (CS, disodium cromoglycate) is an antiasthmatic and antiallergenic drug. The solid-state behavior of CS is still not completely understood. CS forms nonstoichiometric hydrates and sorbs and liberates water in a continuous manner, although with hysteresis. The reported continuous changes in crystal lattice parameters of CS, which are associated with the changes in water stoichiometry, renders CS physically variable, which may complicate formulation and processing. In addition, controversies still remain as to whether CS exists as different stoichiometric hydrates, mainly because of its variable powder X-ray diffraction (PXRD) patterns (Cox, J. S. G. et al. J. Pharm. Sci. 1971, 60, 1458-65), which indicates a variable crystal structure. The objectives of this study are (a) to understand this unusual water uptake in the light of the molecular and crystal structures of CS, (b) to understand the relationship between the crystal structure and the PXRD patterns using Rietveld analysis, and (c) to investigate whether CS exists as different stoichiometric hydrates. The crystal structure of CS containing 6.44 molecules of water per molecule of CS was determined at 295 and 173 K. The packing arrangements in these structures (space group P1) are similar to those in a previous report, in which the water stoichiometry is 5 to 6, but the bond lengths, bond angles, and lattice parameters are different, reflecting the different water stoichiometries. In the crystal structure solved at 295 K, the position of only one of the two sodium ions could be determined. In the crystal structure solved at 173 K, the previously undetermined sodium ion is disordered over three sites, while four of eight water positions are partially occupied. The 2-hydroxy-propane chain that links the two cyclic moieties of CS was found to be flexible, perhaps allowing the CS crystal to accommodate variable amounts of water. The lack of a fixed coordination site for the second sodium ion may contribute to the disorder of the water molecules. The nonstoichiometric water content of CS is mainly attributed to the water molecules that are associated with the two unoccupied sodium sites. From the PXRD patterns of CS powder, equilibrated at various relative humidities, the various lattice parameters, including previously unreported alpha, beta, and gamma values, were calculated using Rietveld analysis. The peak shifts in these PXRD patterns are quantitatively explained by slight changes in the unit cell parameters. The recently described solid forms of CS were prepared and were found to correspond to the original crystalline CS, described by Cox et al. (1971), but with contamination by the known M mesophase in various proportions. The present results support a variable crystal structure and not the existence of different stoichiometric hydrates of CS.

Physical properties of parabens and their mixtures: solubility in water, thermal behavior, and crystal structures.

The peculiar solubility behavior of propylparaben (propyl ester of 4-hydroxybenzoic acid) in aqueous solution, when tested separately and together with methyl-, ethyl-, and butyl-parabens, has been investigated in detail. The results clearly indicate that the decrease in solubility (approximately 50% compared to the solubility value of propylparaben alone) is typical of those mixtures containing also ethylparaben, as demonstrated by solubility experiments on binary, ternary, and quaternary mixtures of the parabens. Phase diagrams of all the six binaries show that propylparaben and ethylparaben are the only pair that form almost ideal solid solutions near the melting temperatures. Moreover, phase-solubility analysis shows that propylparaben and ethylparaben, at room temperature, can also form solid solutions whose solubility is related to the composition of the solid phase at equilibrium. To achieve an independent confirmation of the possible solid solution formation that supports the above interpretation of the solubility behavior, the crystal structures of the four parabens have been examined and isostructurality has been found to exist only between ethylparaben and propylparaben. Powder X-ray diffraction has also been performed on ethylparaben, propylparaben, and their solid solutions obtained by recrystallization from water. The progressive shift of distinctive diffraction peaks with phase composition clearly indicates that propylparaben and ethylparaben form substitutional solid solutions. The small value (<1) of the disruption index provides thermodynamic support for substitutional solid solutions based on isostructural crystals.