Introduction

Paliperidone is primarily used for the treatment of schizophrenia, aiming to improve psychiatric symptoms and abnormal behaviors by modulating the activity of neurotransmitters such as dopamine and serotonin in the brain [1,2,3,4,5]. Compared to risperidone, paliperidone demonstrates higher selectivity and affinity, particularly in its antagonistic effects on serotonin receptors, thereby reducing some common adverse reactions associated with typical antipsychotic medications, such as motor disorders [6,7,8,9,10,11,12].

However, the solubility of paliperidone is relatively low, which may restrict its oral absorption and bioavailability. To overcome this issue, researchers have focused on improving its solubility and drug properties through crystal engineering and co-crystallization techniques [13,14,15,16]. Crystal engineering involves adjusting the structure and intermolecular interactions within the crystal lattice to optimize the solubility and stability of paliperidone. Simultaneously, significant enhancements in solubility can be achieved by forming co-crystals with appropriate acidic substances. The mechanism of crystal formation involves interactions between the drug and acid, such as hydrogen bonding and ion pairing, which can improve the solubility and bioavailability of the drug [17,18,19,20,21,22,23,24,25,26].

Therefore, in this study, we successfully synthesized two pharmaceutical salts of paliperidone, namely paliperidone benzoate (PLPT·BA) and paliperidone salicylate (PLPT·SA), using benzoic acid (BA) and salicylic acid (SA) as starting materials, respectively, through a solvent evaporation method. It is worth noting that the PLPT·BA was previously reported as a co-crystal in a research paper, but no single-crystal structure data or further analysis was provided [27]. In our study, we confirmed the salt structure through ΔpKa calculations, single-crystal structure analysis, and infrared spectroscopy, and evaluated the solubility of the salts. Similarly, we conducted related research on the previously unreported PLPT·SA salt. The TGA–DSC tests revealed a significant enhancement in their thermal stability, with PLPT·BA exhibiting a 39 K increase and PLPT·SA showing a 32 K rise in their decomposition temperatures compared to pure PLPT. Additionally, the SCXRD tests demonstrated the formation of intramolecular charge-assisted hydrogen bonds (N+–H···O) in both PLPT·BA and PLPT·SA. Both salts were found to crystallize in the monoclinic system with the \(P\overline{1}\) (2) space group. Moreover, the dissolution and dissolution rate experiments indicated a slight improvement in their solubility and dissolution rate compared to PLPT.

Synthesis

PLPT was furnished by Changzhou Siyao Pharmaceutical Company, whereas BA and SA were procured from Aladdin Reagent, Inc. All chemical compounds employed in this study were commercially available and demonstrated exceptional purity, thereby negating any necessity for further purification. Scheme 1 graphically depicts the molecular structures of PLPT and the co-formers utilized in this research, along with the respective pKa values of their functional groups under investigation.

Scheme 1
scheme 1

structures of the PLPT and co-formers used in this study and the pKa of their respective groups

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PLPT·BA

PLPT (1 g), along with BA (0.57 g), CH2Cl2 (10 mL), and heptane (50 mL), was combined in a reaction vessel. The mixture was stirred at 40 °C until a clear solution was obtained. Subsequently, solid material was precipitated upon the addition of heptane. The resulting solid was then filtered, dried, and transferred to a test tube. The test tube was sealed, and slow evaporation at room temperature was conducted for 10 days, resulting in the formation of needle-shaped single crystals. These crystals were carefully collected for further analysis.

PLPT·SA

In a 100-mL round-bottom flask, PLPT (1 g) and salicylic acid (0.34 g) were mixed with anhydrous ethanol (30 mL). The mixture was stirred at 60 °C for 1 h and then at room temperature, leading to solid precipitation. The solid was dried, and 0.1 g of it was dissolved in anhydrous ethanol (20 mL). After filtration, the solution was left at room temperature for 15 days, resulting in the emergence of block-shaped single crystals, which were carefully collected for further analysis.

Thermal measurements

A Netzsch TGA–DSC instrument was performed on all samples. Alumina crucibles were employed to hold 8 mg of PLPT, PLPT·BA, and PLPT·SA. The testing temperature range was set from 300 to 1000 K, with a heating rate of 15 K/min and a nitrogen flow rate of 20 mL/min.

pKa calculations

The pKa values of the individual moieties of PLPT, BA, and SA were calculated by the “Calculations” module in the academic version of the software Marvin Sketch 23.8.

PXRD

The substances were exposed to 40 °C/65% relative humidity (RH) for 10 days and subsequently analyzed using powder X-ray diffraction (PXRD) to assess their stability. The Rigaku D/MAX 2000 PC X-ray diffractometer was utilized for collecting the PXRD data. To prepare the samples, PLPT, PLPT·BA, and PLPT·SA were finely ground into powders and evenly distributed onto a sample holder. The scanning range for the 2θ angle was set from 5° to 55°, with a step size of 0.02° and a scanning speed of 5°/min.

Infrared (IR) measurements

The sample was thoroughly ground with potassium bromide, which was spectroscopically pure, in a 1:100 ratio. A small amount of the mixture was then taken and pressed under a pressure of 10 MPa to create a translucent thin sheet. This thin sheet was used for infrared measurement using a Nicolet 5700 Fourier transform infrared (FT-IR) spectrometer. The scanning range covered from 4000 to 400 cm−1, with a resolution of 2 cm−1.

Single-crystal structure determination and calculation

A suitable single crystal was selected for data collection using a Bruker diffractometer. The process was carried out at a controlled temperature of 100(2) K. Subsequently, the crystal structure was analyzed using the SHELXT module in the Olex2 software package [28, 29]. The crystallographic data are presented in Table S1. The aforementioned crystal data can be accessed from the Cambridge Crystallographic Data Centre (CCDC) with the corresponding CCDC numbers 2269579 and 2269580.

Solubility measurements

A standardized procedure is implemented for each of the three different compounds. Solutions with known concentrations and pH values are prepared at 298.15 K, and high-performance liquid chromatography is used to establish the correlation between concentration and absorption peak area. Saturated solutions of the compounds are then prepared and agitated in a shaker for 24 h. The resulting supernatant is extracted and tested to calculate solubility. For pH 6.8, potassium dihydrogen phosphate and sodium hydroxide are dissolved in water and diluted to 1000 mL. For pH 4.0, sodium acetate trihydrate and acetic acid are dissolved in water and diluted to 1000 mL. For pH 1.2, hydrochloric acid is dissolved in water and diluted to 1000 mL.

Dissolution measurements

The dissolution rates of PLPT, PLPT·BA, and PLPT·SA were assessed using the basket method at 310.15 K under varying pH conditions (pH 1.2, pH 4.0, and pH 6.8). A solvent volume of 500 mL was used, and equal quantities of each salt solvate were enclosed in pharmaceutical capsules after measuring 6 mg of pure PLPT. The experimental process involved preparing the dissolution medium, assembling the apparatus, stirring the medium, sampling at specific intervals, analyzing the sample concentrations, recording data, and performing data analysis. To ensure accuracy and reproducibility, each experiment was conducted three times.

Result and discussion

Thermal stability

As shown in Fig. 1, the endothermic melting process was represented by the downward latent heat peak, and the melting points of PLPT decreased from 459 to 424 K and 422 K. This common phenomenon was caused by the reduction of lattice energy due to ion-ion interactions formed during the salt formation process, which resulted in a lowering of the eutectic point. The exothermic decomposition process was observed from the upward exothermic peak, indicating that upon salt formation with BA and SA, their thermal stability was respectively improved by 39 K and 32 K. This enhancement might have been attributed to the fact that the newly formed salts had stronger ion interactions compared to the intermolecular interactions of PLPT, leading to increased crystal stability and providing a longer-lasting stability and activity retention for PLPT storage and usage. We also found that the melting points of the salted PLPT-BA were greater than BA by 29 K and PLPT·SA by 10 K. We also found that the melting points of the salted PLPT-BA were greater than BA by 29 K and PLPT·SA by 10 K. We also found that the melting points of the salted PLPT·BA were greater than BA by 29 K and PLPT·SA by 10 K, respectively. Additionally, the change in thermal stability could be clearly observed from Fig. S1.

Fig. 1
figure 1

DSC curves of PLPT, PLPT·BA and PLPT·SA

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ΔpKa rule

As it is widely known, the ΔpKa rule is used to predict acid–base equilibrium changes in chemical reactions. According to this rule, when there is a significant difference in pKa values between the acid–base pairs of two reactants (usually greater than 3), the stronger acid’s conjugate base is more likely to abstract a proton from the weaker acid’s conjugate base, leading to the formation of a salt. Otherwise, a eutectic mixture might be formed [30,31,32,33,34].

Based on Scheme 1, we can observe that the pKa of the N on the pyridine ring of PLPT is 8.76, while the carboxylic acid groups of BA and SA have pKa values of 4.08 and 2.79, respectively. In both cases, the ΔpKa is greater than 3. Therefore, according to this rule, we can deduce that PLPT·BA and PLPT·SA are both in the form of salts. Further analysis regarding their specific structures will be discussed in the following text.

PXRD analyses

As shown in Fig. 2, the diffraction peaks of PLPT at 2θ angles 7.42° and 10.28° were disappeared, while significant new peaks were observed at 6.9°, 8.08°, and 8.96° for PLPT·BA and at 6.94°, 8.44°, and 9.02° for PLPT·SA. These observations indicate that new and unique crystal structures of the two salts were formed. In addition, we found that a small amount of PLPT peaks appeared in PLPT·BA only at 2θ angles of 8.18°, 11.56°, and 21.7°, respectively, which may be due to a small amount of PLPT mixed in the samples used for the test, but it can still be seen that its purity meets the requirements of the next step of the test.

Fig. 2
figure 2

PXRD test patterns of PLPT, PLPT·BA, and PLPT·SA

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In Fig. 3, the test results and calculations after 10-day storage at 40 °C and 65% relative humidity for both salts are presented. Upon comparison, it was found that the two sets of results were basically consistent, indicating that the salts we prepared were of pure phase and exhibited good stability. They can be used for other characterization experiments with confidence.

Fig. 3
figure 3

Comparison of measured and simulated values of PLPT·BA and PLPT·SA after 10 days at 40 °C and 65% RH

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IR analyses

Through comparative analysis of Fig. 4, we observed that the sharp v(O–H) characteristic peak at 3295 cm−1 in the infrared spectrum of PLPT disappeared. However, in the infrared spectra of PLPT·BA and PLPT·SA, broad peaks appeared around 3415 cm−1 and 3432 cm−1, respectively. These broad peaks are likely attributed to the formation of intramolecular hydrogen bonds corresponding to v(O–H) vibrations. We also found in Fig. 4a and b that the small peaks at 3563.8 cm−1 corresponded to the v(N+–H) vibrations of PLPT-BA, and the small peaks at 3577.3 cm−1 corresponded to the v(N+–H) vibrations of PLPT·SA. In addition, in the magnified enhanced plots of Fig. 4a and b, we found a Vvas (COO−) of 1610.3 cm−1 and a Vvs (COO−) of 1479.134 cm−1 for PLPT-BA. The Vvas (COO−) of 1617.984 cm−1 and a Vvs (COO−) of 1454.064 cm−1 for PLPT·SA. This further confirms the formation of the new salts.

Fig. 4
figure 4

a IR spectra of PLPT, BA, PLPT·BA and a magnified view of the area around wave number 1500; b IR spectra of PLPT, SA, PLPT·SA and a magnified view of the area around wave number 1500

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Crystal structure analyses

Table S1 displays the crystallographic information of PLPT·BA and PLPT·SA, both of which were crystallized in the monoclinic system with the \(P\overline{1}\) P-1 (2) space group. Figure 5 presents the basic structural units of the two substances obtained from the SCXRD analysis. It was observed that both substances involved proton transfer, with protons from the carboxylic groups being relocated to the N atom of the PLPT pyridine, forming intramolecular charge-assisted hydrogen bonds (N+–H···O).

Fig. 5
figure 5

Basic structural units of a PLPT·BA and b PLPT·SA. Ellipsoid rate was set to 50%t level

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Table S2 shows the different types of hydrogen bonds existing intramolecularly and intermolecularly in PLPT·BA and PLPT·SA. Based on the crystal packing diagrams shown in Figs. 6 and 7, it was noticed that besides hydrogen bonds, there were also π···π interactions present in the structures of PLPT·BA and PLPT·SA. The π···π interaction planes in PLPT·BA had a spacing of 3.584 Å and a centroid displacement value of 1.343 Å, while in PLPT·SA, the π···π interaction planes had a spacing of 3.588 Å and a centroid displacement value of 1.178 Å. From these observations, it could be inferred that the crystallographic characteristics of the salts maintained similarities with the parent PLPT, given their similar aromatic carboxylic acid structures.

Fig. 6
figure 6

Crystal stacking diagram of PLPT·BA; red and blue dashed lines represent two different types of hydrogen bonds

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Fig. 7
figure 7

Crystal stacking diagram of PLPT·SA; red and blue dashed lines represent two different types of hydrogen bonds

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Solubility and dissolution analyses

Figure 8 displays the solubility of PLPT, PLPT·BA, and PLPT·SA under various simulated human absorption conditions. It was observed that in pure water, the solubility of PLPT·BA and PLPT·SA increased by 125.81 times and 22.97 times, respectively, compared to PLPT. The increased solubility of salts can be attributed to two primary factors. Firstly, the stronger interaction between the positively charged cations and negatively charged anions of the salt with solvent molecules results in more potent ion–solvent interactions compared to neutral molecules. This heightened electrostatic interaction facilitates salt dissolution. Secondly, hydration plays a crucial role. When salts dissolve, water molecules surround and stabilize the dissociated ions through a process called hydration. This hydration process effectively prevents ion re-aggregation, ensuring that the dissolved salt remains stably dispersed within the solution without re-precipitating. As a result, a stable state of dissolution equilibrium is achieved. At pH 6.8, the solubility of PLPT·BA and PLPT·SA increased by 17.23 times and 5.89 times, respectively. This increase is for essentially the same reason as the increase in solubility in pure water.

Fig. 8
figure 8

Solubility 3D images of compound of PLPT, PLPT·BA and PLPT·SA

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However, at pH 4, the solubility of PLPT·BA slightly decreased, while the solubility of PLPT·SA was only one-sixth of PLPT under the same conditions. This could be attributed to the effect of a similar co-ion inhibition, where a large number of acetate ions suppressed the dissociation of cations and anions in PLPT·SA, thereby affecting its solubility. Meanwhile, at pH 4, PLPT molecules could potentially undergo protonation, leading to an increase in their solubility. At pH 1.2, the solubility of PLPT·BA was 1.08 times higher than that of PLPT. Similarly, due to the influence of a similar co-ion effect, the solubility of PLPT·BA slightly decreased.

Figure 9 presents the dissolution rates of PLPT, PLPT·BA, and PLPT·SA under different pH conditions. It was observed that at pH 6.8, within 20 min, PLPT·BA and PLPT·SA had already dissolved almost completely, while PLPT only dissolved 28.3%. At pH 4, the dissolution rates of PLPT and PLPT·BA were nearly the same, slightly higher than that of PLPT·SA. At pH 1.2, within 10 min, both PLPT·BA and PLPT·SA dissolved almost completely, while PLPT only dissolved 91.76%. Overall, the dissolution rates of PLPT·BA and PLPT·SA were improved compared to PLPT.

Fig. 9
figure 9

Dissolution profiles of PLPT, PLPT·BA, and PLPT·SA at pH 1.2, 4, and 6.8

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Conclusion

In summary, we successfully prepared two salts, PLPT·BA and PLPT·SA, using the solvent evaporation method. This study presents the first-ever reports on their single-crystal structures and, importantly, corrects previous inaccuracies regarding PLPT·BA being labeled as a eutectic compound. The thermal stability of these salts was found to be significantly enhanced, with PLPT·BA exhibiting an increase of 39 K and PLPT·SA showing a rise of 32 K in their decomposition temperatures compared to PLPT. Our analyses based on the ΔpKa rule, IR, and PXRD provided further evidence of the salts’ unique structures and high purity. Remarkably, the SCXRD tests revealed that both PLPT·BA and PLPT·SA form intramolecular charge-assisted hydrogen bonds (N+–H···O) through proton transfer. Additionally, both salts were observed to crystallize in the monoclinic system with the \(P\overline{1}\) P-1 (2) space group, displaying similar π···π stacking arrangements.

Moreover, our solubility and dissolution rate experiments demonstrated a modest yet discernible improvement in their solubility and dissolution rate when compared to pure PLPT. Although these advancements may seem slight, this pioneering work of reporting and investigating the single-crystal structures of PLPT·BA and PLPT·SA establishes a crucial foundation for future investigations into their potential applications in drug formulations and pharmacology. Through further in-depth research on these drug salt crystals, we can gain a deeper understanding of their dissolution mechanisms and drug release behavior, offering more possibilities for tailored and optimized drug formulations. The development of these innovative drug forms holds tremendous promise, presenting new opportunities for enhancing the clinical efficacy and applicability of PLPT in the realm of medicine.