Synthesis of organic HCl salts via mechanochemical salification and their characterization with ^35/37Cl solid-state NMR spectroscopy

Abstract

Hydrochloride (HCl) salts are among the most common solid forms of active pharmaceutical ingredients (APIs) because of their favorable physicochemical properties, including enhanced solubility and stability. However, their syntheses via conventional solution-based methods are often complicated by challenges related to solvent use, stoichiometric control, phase selectivity, and environmental waste. This work presents a novel mechanochemical salification protocol that enables rapid and quantitative syntheses of a variety of organic HCl salts using precise, stoichiometric amounts of HCl. Seventeen salts were prepared from eight organic free base molecules, primarily through mechanochemistry, encompassing hydrates, anhydrous forms, and rare hemihydrochloride phases. Careful consideration is given to a variety of factors affecting these reactions, including the quantity of HCl, solvents of HCl solutions, duration and frequency of milling, the relevance of pK_a and material stability, and upward reaction scalability. Structural characterization was carried out using ^35/37Cl solid-state NMR (SSNMR) spectroscopy and powder X-ray diffraction, which provide detailed insights into the local chloride ion environments and phase purities. Dispersion-corrected density functional theory (DFT-D2*) methods were used to geometry-optimize structural models based on known crystal structures and to establish correlations between ^35/37Cl electric field gradient (EFG) tensors and hydrogen bonding networks essential for stabilization of crystal structures. These results demonstrate the efficiency and precision of mechanochemical salification for generating a diverse array of solid forms, as well as the utility of advanced SSNMR techniques and DFT methods for uncovering subtle structural features that govern the behaviors of salts of APIs.

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1. Introduction

Approximately half of the active pharmaceutical ingredients (APIs) on the market are manufactured as solid, organic HCl salts, often due to their improved physicochemical properties, such as solubility, stability, and bioavailability.^1–4 HCl salts are commonly produced via recrystallization from solution, or in some instances, by exposure to gaseous HCl.^5–16 The synthesis of HCl salts from recrystallization faces several challenges, including: (i) time-consuming evaporations; (ii) use of excessive amounts HCl and other solvents; (iii) the increased likelihood of impurity phases and/or polymorphism due to spatial heterogeneity (i.e., temperature or concentration gradients); and (iv) other confounding factors that are difficult to control precisely, such as inadvertent seeding from residual solids or metastable nuclei, which can bias crystallization pathways and complicate reproducibility.^17–19

Mechanochemistry offers better alternatives for the production of solid forms of APIs, offering advantages such as quantitative yields, minimal impurities, and short timescales (i.e., minutes to hours).^20–22 Furthermore, mechanochemical reactions are often readily scalable, allowing processes developed on a small laboratory scale to be translated to large-scale industrial production.^23–28 While mechanochemical methods have been used to produce a variety of solid forms of organic molecules (e.g., cocrystals, salts, solvates, etc.), there are currently no reported examples of mechanochemical synthesis of organic salts using free bases and inorganic acids (e.g., HCl, HBr, H₂SO₄, etc.), which is surprising, given their widespread use as the preferred solid forms for many APIs. As such, mechanochemical salification techniques are expected to be of significant interest to academic and industrial researchers alike.

Mechanochemistry encompasses a diverse range of reaction types, with each potentially offering unique pathways for solid-state transformations. Among the most common techniques is ball milling,^21,29 in which reagents are placed into a milling jar with ball bearings and ground at a specific frequency for a fixed duration. In many cases, a small amount of liquid is added to accelerate or enable the reaction – this is known as liquid assisted grinding (LAG),^30,31 whereas milling without liquid is known as neat grinding (NG). For larger scale reactions, mechanochemical methods such as resonant acoustic mixing, speed mixing, planetary milling, and twin-screw extrusion are increasingly employed in industrial settings to produce a variety of products, including pharmaceuticals, agrochemicals, catalysts and other advanced materials.^23,32–35 In all cases, the solvent-free or low-solvent processes enhance efficiency and sustainability, representing true instances of solid-state syntheses that adhere to the principles of green chemistry.^36,37

The products from ball milling reactions tend to be microcrystalline powders, which hinder the use of single-crystal X-ray diffraction (SCXRD) for their characterization. However, several other analytical techniques enable their characterization, including powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), IR and Raman spectroscopies, and solid-state NMR (SSNMR) spectroscopy, among others.^38–46

Both ³⁵Cl and ³⁷Cl (spin I = 3/2) SSNMR are well established for characterizing HCl salts of organic molecules, including APIs, since their spectra have broad, central transition (CT, +1/2 ↔ −1/2) powder patterns that typically range from tens to hundreds of kHz in breadth, due to influences from the second-order quadrupolar interaction (SOQI) and chemical shift anisotropy (CSA).^1,47–55 The quadrupolar interaction (QI) describes the coupling between the nuclear quadrupole moment and the electric field gradient (EFG) at the nuclear origin, the latter of which is described by a symmetric, traceless, second-rank tensor. ^35/37Cl EFG tensors of chloride ions in organicHCl salts are extremely sensitive to their local environments.^1,47,54–61 Since they can easily be determined from ^35/37Cl SSNMR spectra via measurement of the quadrupolar coupling constant, C_Q, and the quadrupolar asymmetry parameter, η_Q, they act as excellent probes of the complex hydrogen bonding environments of chloride ions, providing unique spectral fingerprints, permitting facile detection of impurity phases, and even enabling quadrupolar guided NMR crystallography-crystal structure prediction (QNMRX-CSP) methods for structural determination and refinement in the absence of SCXRD data.^62,63

Despite having a larger nuclear quadrupole moment (Q) than ³⁷Cl, ³⁵Cl is typically the nucleus of choice for SSNMR experimentation due to its higher gyromagnetic ratio (γ) and higher natural abundance (n.a.). Nonetheless, ³⁷Cl SSNMR can play a complementary role due to its distinct values of γ and Q, allowing for the precise determination of the EFG and CS tensors via measurement of both ³⁵Cl and ³⁷Cl NMR spectra at a single magnetic field.^{48,49,64–70} Furthermore, the C_Q(^35/37Cl) values of the chloride ions in organic HCl salts range from hundreds of kHz to ca. 10 MHz, meaning that ^35/37Cl SSNMR spectra featuring well-defined CT patterns can be acquired with relative ease, even at lower magnetic field strengths.

Herein, we discuss efficient mechanochemical salification of eight solid free base molecules (Scheme 1) to produce sixteen HCl salts (eleven previously known and five newly discovered, Table 1), the formation of a novel salt of picolinamide produced via slow evaporation, and the structural characterization of all seventeen salts. We demonstrate the (i) advantages of mechanochemistry, including solid form discovery and scalability; (ii) influence of key mechanochemical parameters on reaction outcomes; (iii) relevance and limitations of solution-based synthetic principles in their application to solid-state chemical transformations; (iv) use of ^35/37Cl SSNMR to investigate structure, phase identity, and sample purity; and (v) application of dispersion-corrected plane-wave DFT methods to evaluate the influence of hydrogen-bonding networks on ^35/37Cl EFG tensors, and how, in turn, they provide insight into complex, solid-state, molecular structures shaped by hydrogen bonding and other weak intermolecular interactions.

Scheme 1 Free base molecules relevant to this work.

Table 1 Optimized conditions and ball milling parameters that lead to quantitative syntheses of each material

Material	Type of HCl used (solvent)^a	Amount of HCl (molar equiv.)	Milling time (minutes)
a In instances where 12.1 M HCl(aq), 3.0 M HCl(MeOH), or 1.5 M HCl(EtOH) can be used, the 12.1 M HCl(aq) is preferred, due to the smaller volume of solvent.b All LAG reactions used a milling frequency of 20 Hz, with the exception of those for IsoH-Iso:H2O and IsoH, for which used a milling frequency of 30 Hz.c Produced only via slow evaporation.d Novel organic HCl salt, not previously reported.
NicH-Nic:H2O	Aqueous	0.5	5
NicH	Aqueous	1	5
IsoH-Iso:H2O^b^,^d	Aqueous	0.5	2
IsoH^b	Aqueous	1	2
PicH-Pic^d	Aqueous	0.5	10
PicH:H2O^c^,^d	Aqueous	—	—
PicH^d	Aqueous	1	5
NicAH	Aqueous	1	5
IsoAH	Aqueous	1	5
PicAH-PicA^d	Aqueous	0.5	10
PicAH:H2O	Aqueous	1	10
PicAH	Methanol	2	15
CaffH:H2O	Aqueous	1	5
CaffH	Methanol	1	5
AcetH-Acet	Methanol	0.5	5
AcetH:H2O	Aqueous	2	5
AcetH-Acet:H2O^d	Aqueous	1	5

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2. Experimental

2.1 Materials

Nicotinic acid (NicA), isonicotinic acid (IsoA), picolinic acid (PicA), acetaminophen (Acet), nicotinamide (Nic), isonicotinamide (Iso), picolinamide (Pic), and caffeine (Caff) (Scheme 1) were purchased from MilliporeSigma and used without further purification. These reagents were used to mechanochemically synthesize eleven previously-reported salts, including: nicotinamide hemihydrochloride hydrate (NicH-Nic:H₂O), nicotinamide HCl (NicH), isonicotinamide HCl (IsoH), nicotinic acid HCl (NicAH), isonicotinic acid HCl (IsoAH), picolinic acid HCl monohydrate (PicAH:H₂O), anhydrous picolinic acid HCl (PicAH), caffeine HCl dihydrate (CaffH:H₂O), caffeine HCl (CaffH), bis(acetaminophen) HCl (AcetH-Acet), and acetaminophen HCl monohydrate (AcetH:H₂O).^7–15 In addition, they were also used to produce six novel salts, including: isonicotinamide-isonicotinamidium chloride monohydrate (Iso-IsoH:H₂O), picolinamide HCl monohydrate (PicH:H₂O), picolinamide HCl (PicH), picolinamide-picolinamidium chloride (PicH-Pic), picolinic acid hemihydrochloride (PicAH-PicA), and (bis)acetaminophen HCl monohydrate (Acet-AcetH:H₂O).

2.2 Synthesis of HCl salts

HCl salts were synthesized using slow evaporation and/or mechanochemical grinding. Mechanochemical syntheses were carried out under a variety of conditions using 12.1 M HCl(aq), 3.0 M methanolic HCl (HCl(MeOH)), or 1.25 M ethanolic HCl (HCl(EtOH)) as milling liquids. Ball milling reactions used 10 mL Teflon milling jars with one 10 mm Teflon ball bearing and were conducted using a Retsch Mixer Mill 500 Vario with a milling frequency ranging from 20 to 35 Hz, and milling times ranging from 2 to 15 min (unless specified otherwise). For larger scale reactions conducted with 75 or 100 g of solids, a FlackTek Model 330-100 SE speed mixer was used with 250 mL polypropylene sample holders at 2000 rpm for 2 minutes. The optimized milling conditions for efficient, high-yield, lab-scale syntheses are presented in Table 1. No further grinding of reaction products was needed prior to analyses by SSNMR or PXRD. For syntheses via slow evaporation, a solution containing one organic reagent was dissolved in a 20 mL glass vial with gentle heating at ca. 55 °C to completely dissolve the solids. The solutions were allowed to evaporate for several days to weeks under ambient conditions. Suitable crystals were used for analysis by SCXRD.

2.3 Powder X-ray diffraction

PXRD patterns were acquired on a Rigaku Miniflex with a Cu Kα (λ = 1.540593 Å) radiation source and a HyPix-400 MF 2D hybrid pixel array detector. The X-ray tube voltage and amperage were set to 40 kV and 15 mA, respectively. Experiments were run with the detector scanning 2θ angles from 2.5° to 50° with a step size of 0.03° at a speed of 5° min⁻¹. The PXRD patterns for all reagents and cocrystals were compared to patterns simulated from reported structural models^{7–15,71–80} using the CrystalDiffract⁸¹ software package to confirm crystallinity and purity, and to identify novel phases (Fig. S1–S7).⁸¹

2.4 Single-crystal X-ray diffraction

A clear light yellow, irregular shaped crystal of PicH:H₂O was mounted on a nylon loop with perfluoroether oil. The sample was crystallized by a diffusion method. Data were collected from a shock-cooled single crystal at room temperature on a XtaLAB Synergy, Dualflex, HyPix four-circle diffractometer with a micro-focus sealed X-ray tube using a mirror as monochromator and a HyPix detector. The diffractometer was equipped with an Oxford Cryostream 800 low-temperature device and used Cu Kα radiation (λ = 1.54184 Å). All data were integrated with Crysalispro and a Gaussian absorption correction using SCALE3 ABSPACK was applied. The structure was solved by dual methods using SHELXT⁸² and refined by full-matrix least-squares methods against F² by SHELXL.⁸³ All non-hydrogen atoms were refined with anisotropic displacement parameters. All C-bound hydrogen atoms were refined isotropic on calculated positions using a riding model with their U_iso values constrained to 1.5 times the U_eq of their pivot atoms for terminal sp³ carbon atoms and 1.2 times for all other carbon atoms. Disordered moieties were refined using bond lengths restraints and displacement parameter restraints. Crystallographic data for the structure reported in this paper has been deposited with the Cambridge Crystallographic Data Centre under the deposition number 2341820.

2.5 Thermogravimetric analysis

Thermogravimetric analysis (TGA) measurements were performed on a TA Instruments TGA 550 with samples packed in alumina crucibles. Samples were heated from room temperature (∼23 °C) to 400 °C at a heating rate of 10 °C min⁻¹ under a dry argon purge (gas flow of 25 mL min⁻¹).

2.6 Solid-state NMR spectroscopy

2.6.1 Overview. SSNMR experiments were conducted at the National High Magnetic Field Laboratory (NHMFL) in Tallahassee, FL. Experiments at B₀ = 18.8 T [ν₀(¹H) = 800.13 MHz, ν₀(³⁵Cl) = 78.42 MHz, and ν₀(³⁷Cl) = 65.35 MHz] were conducted on Bruker Avance NEO spectrometer with an Oxford standard bore magnet. Magic-angle spinning (MAS) and static (stationary sample) experiments were carried out with NHMFL-built 5.0 mm HX or 3.2 mm HXY probes, with samples packed into 3.2 zirconia oxide rotors (³⁵Cl static/MAS) or 5.0 mm o.d. polychlorotrifluoroethylene sample holders (³⁷Cl static).

2.6.2 ^35/37Cl SSNMR. Static ³⁵Cl{¹H} SSNMR spectra were obtained at 18.8 T using a variety of pulse sequences (Hahn Echo,⁸⁴ QCPMG,^85–87 CP-CPMG,^88–90 and WURST-CPMG^91–93) with a continuous wave (CW) ¹H decoupling field of 50 kHz. All WURST pulses used a 500 kHz sweep width. ³⁷Cl{¹H} static spectra were obtained using Hahn Echo, QCPMG, or CP-CPMG pulse sequences, with CW ¹H decoupling field of 50 kHz. ³⁵Cl{¹H} MAS spectra were obtained using a Bloch decay or rotor-synchronized Hahn Echo or QCPMG pulse sequence, with an MAS rate of ν_rot = 10–20 kHz and 50 kHz of SPINAL-64 deocupling.^{94–96 35/37}Cl chemical shifts were referenced to 1.0 M NaCl(aq) (δ_iso = 0.0 ppm) using NaCl(s) (δ_iso = −41.1 ppm) as a secondary reference. Experimental details are provided in Tables S1 and S2. Pulse sequences and recommended calibration parameters and standards are available from the authors by request or at https://github.com/rschurko.

2.6.3 Spectral processing and simulation. Spectra were processed using the TopSpin v.3.7 software package. Simulations of ^35/37Cl SSNMR spectra were generated using the ssNake v.1.5 software package.⁹⁷ Euler angles extracted from simulations in ssNake, which use the ZX′Z″ convention, were converted to the ZY′Z″ convention and verified through additional simulations in WSolids1.^98,99

2.7 DFT calculations

Calculations were performed on structural models based on previous SCXRD studies,^{7–15,71,100} with the exception of PicH:H₂O, for which the structural model is based on the SCXRD structure reported herein. Geometry optimizations and subsequent calculations of ³⁵Cl EFG and magnetic shielding tensors were performed using dispersion-corrected plane-wave DFT methods (DFT-D2*)^101,102 using the CASTEP module^103,104 within Materials Studio 2020. These calculations used the generalized gradient approximation (GGA) with the RPBE functional,¹⁰⁵ ultrasoft pseudopotentials generated on-the-fly,¹⁰⁶ a k-point spacing of 0.05 Å⁻¹, a plane-wave cut-off energy of 800 eV, and an SCF convergence threshold of 5 × 10⁻⁷ eV. Geometry optimizations employed the LBFGS method,¹⁰⁷ in which the positions of all atoms were relaxed with unit cell parameters fixed at their experimental values. Thresholds for structural convergence included a maximum change in energy of 5 × 10⁻⁶ eV per atom, a maximum displacement of 5 × 10⁻⁴ Å per atom, and a maximum Cartesian force of 10⁻² eV Å⁻¹. A correction to the dispersion energy was introduced using Grimme's semi-empirical two-body dispersion force field,^108,109 with an empirical reparameterization introduced by our group.^{101,102,110 35}Cl magnetic shielding tensors were calculated using the GIPAW method.^{111 35}Cl chemical shift values were referenced with respect to that of NaCl(s) (δ_iso = −41.1 ppm), which has an absolute isotropic magnetic shielding value of 993.28 ppm. EFGShield¹¹² was used to extract the Euler angles describing the relative orientations of magnetic shielding and EFG tensors, which are reported using the ZY′Z′′ convention for rotation.⁹⁹

3. Results and discussion

3.1 Overview

In this section, we discuss: (i) the mechanochemical syntheses of previously reported and novel organic HCl salts; (ii) considerations for their optimized mechanochemical syntheses; (iii) their characterization using SSNMR, XRD, and TGA; and (iv) DFT-D2* calculations for refinement of crystal structures and prediction of ^35/37Cl EFG tensors. ^35/37Cl SSNMR is highlighted as the key characterization method due to the unique ^35/37Cl CT powder patterns resulting from the diverse hydrogen bonding arrangements of the chloride ions in organic HCl salts. DFT calculations are used to correlate the ³⁵Cl EFG tensors to the local hydrogen bonding environments of the chloride ions, which is crucial for understanding their roles in stabilizing their solid-state structures.

The outcomes of all mechanochemical syntheses were assessed using PXRD data, with patterns acquired for all previously reported and novel organic HCl salts (Fig. S1–S7). Those of the former are in good agreement with simulated patterns based on their crystal structures, while those of the latter are compared to patterns of educts, with distinct diffraction peaks attributed to novel phases (based on this, the stoichiometry of the reaction, and no detection of impurities via PXRD and/or other analytical techniques, vide infra). The PXRD pattern of PicH:H₂O was also compared to simulated patterns derived from the novel crystal structure reported herein and found to be in agreement. These results confirm that the syntheses are successful, and the products are crystalline with no presence of impurities.

3.2 Mechanochemical salification methods for the synthesis of organic HCl salts

Eleven known and five novel organic HCl salts were synthesized in essentially quantitative yields and high purities via mechanochemical salification, and one novel organic HCl salt was produced via slow evaporation, as evidenced by PXRD (referred to throughout Section 3.2) and ³⁵Cl SSNMR (see Section 3.6.3). Optimized LAG conditions and ball milling parameters are reported in Table 1. Generally, the role of ball milling appears to be that of mixing of reagents, consistent with the acid–base neutralization reactions that often occur spontaneously for such systems. However, there are many factors that play a role in the formation of the desired salt with minimal impurities and waste, as discussed in the text that follows.

3.2.1 Impact of the quantity of HCl. In most solution-based salification reactions, HCl is added in significant excess (e.g., fully dissolving a solid free base in concentrated HCl);^7,8 however, with mechanochemical methods, it is possible to use microliters of solvent in precise molar ratios to target specific products. Generally, if multiple solid phases differ in their chloride content, the relative stoichiometry of HCl governs which phase is obtained. For example, NicH-Nic:H₂O and NicH were both synthesized via LAG using precise stoichiometric amounts of 12.1 M HCl(aq) to target the desired product (i.e., half an equivalent was used for NicH-Nic:H₂O, whereas one equivalent was used for NicH). If more than half an equivalent of HCl is added, the formation of NicH is favored due to preferred protonation of the pyridyl nitrogen. A slight excess of acid can also facilitate the synthesis of a specific product by preventing side reactions or driving the reaction forward in cases where optimizing other synthetic parameters is unfeasible (e.g., in the salification reactions that yield AcetH:H₂O and PicAH, two equivalents of HCl is used to eliminate impurities and/or unreacted educts).

3.2.2 Impact of the solvent of HCl solutions. The choice of solvent can have a considerable impact on mechanochemical reactions.^31,113–115 Herein, three distinct solvents were used for concentrated HCl solutions, including 12.1 M HCl(aq), 3.0 M methanolic HCl (HCl(MeOH)) and 1.25 M ethanolic HCl (HCl(EtOH)). In the cases of PicA, Caff, and Acet, the solvent determines which salt is formed. Use of HCl(aq) leads to the production of the hydrates PicAH:H₂O, CaffH:H₂O, and AcetH:H₂O, whereas use of HCl(MeOH) or HCl(EtOH) leads to the formation of the anhydrous salts PicAH, CaffH, and AcetH. This contrasts with the case of NicA, where the solvent is relatively unimportant, as NicAH appears to be the only possible product (i.e., no hydrate or solvate phases have been observed in our reaction product mixtures). The use of different HCl solvents also offers insights into the nature of the products. For example, PicAH-PicA was determined to be anhydrous due to the identical products obtained from reactions involving either HCl(aq) and HCl(MeOH). Similarly, IsoH-Iso:H₂O was determined to be a hydrate, since use of half an equivalent of HCl(MeOH) produced a mixture of IsoH and unreacted Iso.

Hence, altering both the amount of HCl and its solvent offers additional pathways for synthesizing novel materials. In certain cases, different HCl solvents may result in different reaction mechanisms that either lead to the same product, or perhaps a distinct polymorph or solvate.^{25,31,55,116–119} As such, it is possible that other systems may exhibit even more complex behavior. However, use of HCl(aq) is generally preferred, since its high HCl concentration is associated with significantly less solvent in comparison to concentrated alcoholic HCl (e.g., in the preparation of 100 mg of NicH, 70 µL of HCl(aq) is necessary, which corresponds to ca. 300 µL of HCl(MeOH) or 700 µL of HCl(EtOH)). However, methanol and ethanol are more easily evaporated than water, given that they are ca. five and two times as volatile under standard temperature and pressure (this is based on calculations using the Clausius–Clapeyron equation, assuming boiling points of 64.7, 78.4, and 100.0 °C for MeOH, EtOH, and H₂O, respectively).

3.2.3 Impact of milling duration and milling frequency. Two important considerations for almost all ball milling reactions are the milling duration and milling frequency. Generally, a sufficient milling duration is required to drive the reaction to completion and ensure formation of the desired products, whereas the milling frequency impacts the rate of the reaction. In most of the cases presented herein, milling at 20 Hz for 5 to 15 minutes is sufficient for the formation of an HCl salt with no trace of educts (i.e., unreacted free bases) or other impurities. However, as the milling duration or milling frequency increases, the temperature inside the milling jar increases as well, which may impact the reaction and end products.¹²⁰

Heating hydrates of organic HCl salts sometimes results in the release of water, leading to an anhydrous solid. For example, excess heating of CaffH:H₂O causes dehydration and disproportionation to Caff, releasing H₂O and HCl.¹²¹ This effect can be replicated in LAG reactions intended for the production of CaffH:H₂O, where milling at a higher frequencies and/or longer durations results in the presence of Caff impurities.

The synthetic pathways for the various HCl salts of PicA (Fig. 1) highlight the heat-dependent transformation of PicAH-H₂O to PicAH-PicA. If the desired product is PicAH:H₂O, the formation of PicAH-PicA needs to be prevented. There are several options to accomplish this, all of which can be used in tandem: (i) addition of excess HCl(aq) causes any PicAH-PicA that is formed to convert to PicAH:H₂O; (ii) use of cryogens can be employed to avert the buildup of heat, preventing the formation of PicAH-PicA; and (iii) reducing the milling time and/or frequency can be used to decrease the time the material is exposed to heat and/or reduce the rate of heat generation. Other parameters also impact the maximum temperature reached, such as the materials of the jar and ball bearings, as well as the amount of material being milled. These are very important considerations for scaling up the reaction size for industrial production.¹²⁰

Fig. 1 Synthetic pathways for producing solid forms of picolinic acid (PicA), where, PicAH = picolinic acid hydrochloride, PicAH:H₂O = picolinic acid hydrochloride monohydrate, and PicAH-PicA = picolinic acid hemihydrochloride.

3.2.4 Impact of pK_a and material stability – an investigation using competitive milling. The protonation behavior of the molecules in Scheme 1 is strongly influenced by their functional groups and positions on the pyridyl ring. Amide groups, such as those in Nic, Iso, and Pic, act as weak electron-withdrawing substituents, which decreases the basicity of the pyridyl nitrogen and makes protonation less favorable in comparison to an unsubstituted pyridyl ring (e.g., pK_a's of the pyridyl nitrogen are 3.4 and 5.2 for Nic and pyridine, respectively). Similarly, carboxylic acid moieties, such as those in NicA, IsoA, and PicA, serve as stronger electron-withdrawing groups, further reducing the basicity of the pyridyl nitrogen and making protonation even less favorable. The position of the substituent relative to the pyridyl nitrogen also plays a key role in modulating electronic effects. Electron-withdrawing groups positioned closer to the pyridyl nitrogen exert a stronger inductive effect, as in the case of Pic, where electron density is withdrawn more effectively from the pyridyl nitrogen than in Nic or Iso. Furthermore, substituents in the ortho and para positions engage in resonance with the pyridyl ring, resulting in a greater reduction in basicity than would be predicted from inductive effects alone.

To investigate the impact of these effects in the context of mechanochemical salification, we conducted a series of competitive milling reactions (Table 2).^122,123 An equimolar amount of two free bases (e.g., Nic and NicA) were added to a milling jar with either one or half a molar equivalent of HCl(aq), and ball milled. The product was then characterized to determine which phase(s) of material is(are) formed. The pK_a values for the six starting materials are in Table S3 (ref. 124) and the PXRD patterns for the reaction products are given in Fig. S8–S18.

Table 2 Results of competitive milling reactions involving two free bases and 12 M HCl(aq)^a

Free bases (1 : 1)	pKa-1^b	pKa-2^b	Amount of HCl (aq) (molar equivalents)	End products^c	Corresponding PXRD figure in SI
a All milling reactions were carried out with a milling rate of 35 Hz and milling time of 30 min, with the exception of Iso + IsoA reactions, which used 30 Hz and 60 min.b pKa-1 and pKa-2 refer to the free bases on the left and right, respectively, in column 1.c Reaction products are indicated in boldface.d Minor phase, significantly less of this solid form is present.e Novel ionic cocrystal with unknown stoichiometry and solvation status.
Nic + NicA	3.35	2.08	1	NicH + NicA	S8
Nic + NicA			0.5	NicH-Nic:H2O + NicA	S8
Iso + IsoA^a	3.61	1.70	1	IsoH + IsoA	S9
Iso + IsoA^a			0.5	IsoH-Iso:H2O + IsoA	S9
Pic + PicA	2.10	1.60	1	PicAH-PicA + Pic-PicA	S10
Pic + PicA			0.5	PicAH-PicA + Pic-PicA	S10
Nic + Iso	3.35	3.61	1	IsoH-Iso:H2O + Nic-Iso + Nic	S11
Nic + Iso			0.5	Nic-Iso	S11
Nic + Pic	3.35	2.10	1	NicH-Nic:H2O + Nic-Pic	S12
Nic + Pic			0.5	Nic-Pic + Pic	S12
Iso + Pic	3.61	2.10	1	Iso-Pic:HCl + Pic^e	S13
Iso + Pic			0.5	Iso-Pic:HCl + Pic^e	S13
NicA + IsoA	2.08	1.70	1	NicAH + IsoA + IsoAH^d	S14
NicA + IsoA			0.5	NicAH + IsoA + NicA	S15
NicA + PicA	2.08	1.60	1	NicAH + PicAH:H2O + NicA + PicA	S16
NicA + PicA			0.5	PicAH:PicA + NicA + PicAH:H2O^d	S17
IsoA + PicA	1.70	1.60	1	PicAH:H2O + IsoA	S18
IsoA + PicA			0.5	PicAH-PicA + IsoA	S18

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The enthalpies of formation (ΔH_f, Table S4) were derived from the equation:

ΔH_f = H_product − (AH⁽¹⁾_educt + BH⁽²⁾_educt + CH_water) (1)

where H_product, H_educt, and H_water correspond to the DFT-derived static lattice energies of the products, educts, and water, respectively, and the coefficients A, B, and C correspond to the stoichiometric amounts of each educt and water, where H_water is only considered for hydrates. While many of the values of ΔH_f are only slightly negative or even positive, there are several possible explanations for why the reaction still proceeds: (i) some portion of the solid is dissolved, which is not captured in static lattice energy models;²¹ (ii) the reaction may be driven through product precipitation, which shifts the equilibrium irreversibly forward;³¹ (iii) there are relatively large errors in these calculated values as finite temperature effects are not taken into account;^125–127 and (iv) mechanochemical effects, such as defect formation and local heating, contribute additional energy to drive the reaction forward.^128,129

First, the competitive milling reactions of mixtures of amides and carboxylic acids with HCl are considered. For Nic, NicA, Iso, and IsoA, the reactions proceed as expected, where the more basic Nic and Iso molecules are protonated instead of NicA and IsoA (i.e., only NicH and IsoH are formed, perhaps due to the higher pK_a's of their pyridyl nitrogens). However, similar reactions with Pic and PicA yield the salt PicAH-PicA, as well as a picolinamide picolinic acid cocrystal (Pic-PicA),¹³⁰ meaning that Pic reacts with the weak acid PicA, rather than the significantly stronger HCl. Without a crystal structure for Pic-PicA, it is difficult to say whether this is a result of a kinetically-favored reaction or if the cocrystal is more thermodynamically stable than PicH, PicH:H₂O, PicAH, and/or PicAH:H₂O.

Second, reactions of mixtures of amides with HCl are discussed. Both the 1 : 1 : 1 and 1 : 1 : 0.5 reactions of Nic, Iso, and HCl yield a nicotinamide-isonicotinamide cocrystal (Nic-Iso).¹³⁰ This is interesting, as the ΔH_f for Nic-Iso is significantly higher than that of NicH or IsoH, meaning a less thermodynamically favorable product is formed. We observe the salt IsoH-Iso:H₂O and excess Nic in the 1 : 1 : 1 case, suggesting that excess acid is needed to drive the reaction forward. Similarly, reactions of Nic, Pic, and HCl yield NicH-Nic:H₂O as well as a nicotinamide-picolinamide cocrystal (Nic-Pic),¹³⁰ further highlighting the possibility of kinetically driven reactions. We also note that NicH-Nic:H₂O is formed in the 1 : 1 : 1 reaction, suggesting that Nic-Pic formation competes poorly under these conditions in comparison to Nic-Iso and Pic-PicA. The reactions of Iso, Pic, and HCl result in the production of an unknown solid form, which is suspected to be an ionic cocrystal of Iso, Pic, and HCl (Iso-Pic:HCl) as evidenced by a unique ³⁵Cl SSNMR spectrum (see Section 3.6.3, Fig. S19), but this is not explored further in this work. However, since there is PXRD evidence of unreacted Pic in the final reaction mixture, it is likely that this cocrystal does not have a 1 : 1 : 1 stoichiometric ratio of the three components.

Finally, the reactions of mixtures of carboxylic acids with HCl are explored. NicA, IsoA, and HCl react in a 1 : 1 : 1 ratio to form NicAH and IsoA; however, some IsoAH is also observed, whereas the 1 : 1 : 0.5 reaction yields NicAH as the only salt, with excess IsoA and NicA. However, the 1 : 1 : 1 NicA + PicA + HCl reaction yields NicAH, PicAH:H₂O, and educts, whereas the 1 : 1 : 0.5 reaction yields PicAH-PicA, PicAH:H₂O, and residual NicA. Both reaction ratios for IsoA, PicA, and HCl yield PicAH:H₂O as the only salt (plus residual IsoA).

In these competitive milling reactions, neither the pyridyl nitrogen basicity (as predicted by pK_a) nor thermal stabilities are the sole predictors of the products. Even the assumption that one of these educts would react with HCl is sometimes incorrect, as seen by the formation of the Pic-PicA, Nic-Iso, and Nic-Pic cocrystals. In mechanochemical reactions, there are additional factors to consider. First, there are clear limitations of using pK_a values to predict the outcomes of solid-state reactions, since they are derived from solution measurements, and do not account for the array of additional solid-state interactions, including intermolecular hydrogen bonding and molecular packing that influence intrinsic basicity/acidity. Second, since mechanochemical reactions involving organic compounds are thought to initiate on the surfaces of particles that are being ground or sheared together,^131–133 it is possible that some reactions are kinetically driven, which may supplant simple considerations of acidity, basicity, and/or thermodynamics. While we are unable to provide a succinct and satisfying explanation for these phenomena, it is clear that predictions based on simple solution-phase principles do not apply to mechanochemical reactions; nonetheless, this opens a wider canvas for exploration of the production of HCl salts and related cocrystals.

3.3 Mechanochemical screening of novel phases of hemihydrochloride salts

High-throughput recrystallizations are often preferred for screening due to the relative ease of setting up many reactions under a variety of synthetic conditions.^134,135 However, mechanochemistry may have an edge in discovering more unusual phases in situations where the stoichiometric ratio of the organic free base (FB) to the number of chloride ions is greater than 1 : 1, such as in the case of hemihydrochloride salts (e.g., FB : HCl = 1 : 0.5, like in the cases of IsoH-Iso:H₂O, PicAH-PicA, etc.). For example, NicH-Nic:H₂O was first synthesized via a two-step slow evaporation over the course of several weeks.⁷¹ However, we report its quantitative synthesis in as little as 2 min, with no detectable byproducts or impurities. The ability to target specific molar ratios with HCl in various solvents allows for facile screening using mechanochemical methods and the exploration of novel solid forms.

3.4 Syntheses of novel HCl salts

Here, we discuss the mechanochemical syntheses of five novel materials: IsoH-Iso:H₂O, PicH-Pic, PicH, PicAH-PicA, AcetH-Acet:H₂O, along with the formation of PicH:H₂O via slow evaporation (reaction summaries are again given in Table 1). The hemihydrochloride salts (i.e., IsoH-Iso:H₂O, PicH-Pic, PicAH-PicA) were synthesized with ratios of 1 : 0.5 FB : HCl. We also attempted to prepare these materials with 12.1 M HCl(aq) or 3.0 M HCl(MeOH) to confirm their hydration states, finding that either solvent led to the formation of PicH-Pic and PicAH-PicA, whereas only HCl(aq) led to IsoH-Iso:H₂O. PicH can be formed with a 1 : 1 ratio of FB : HCl with either HCl(EtOH) or HCl(MeOH), suggesting that it is anhydrous. Ball milling Acet and 12.1 M HCl(aq) in a 1 : 1 molar ratio yields what we suspect to be AcetH-Acet:H₂O, since a 1 : 2 ratio yields AcetH:H₂O and a 1 : 0.5 ratio yields a mixture of Acet and AcetH-Acet:H₂O (Fig. S20). Due to the relatively poor basicity of the secondary amide, it is unclear whether AcetH-Acet:H₂O is a hemihydrochloride requiring optimized milling conditions, if it is a polymorph of AcetH:H₂O, or if it exists in a unique, non-standard molar ratio. While mechanochemical methods alone cannot give a definitive answer on the nature of this material, TGA can (see Section 3.6.1).

The synthesis of PicH:H₂O is unique in this work, being non-mechanochemical. Two equivalents of HCl(aq) are enough to fully dissolve Pic while milling, with subsequent evaporation of excess solvent leading to the formation of PicH:H₂O. The formation of this material is likely better suited for slow evaporation, as straightforward milling of PicH with different molar equivalents of H₂O does not lead to the formation of PicH:H₂O. This slow evaporation synthesis yielded crystals suitable for SCXRD structure determination (see Section 3.6.1).

3.5 Mechanochemical scale-up

The mechanochemical salification methods outlined herein have the potential to be used on an industrial scale. To explore this, a speed mixer was used with larger quantities of free base solids and 12.1 M HCl(aq) to produce NicH, NicH-Nic:H₂O, NicAH, and CaffH in amounts between 75 and 100 g in quantitative yields (i.e., no detectable educts or impurities in the PXRD patterns, Fig. S21) in as little as 2 minutes at 2000 rpm (Table 3, first four rows). This was accomplished using the same reaction chemistries listed in Table 1, with near stoichiometric amounts of HCl and no ball bearings. Further reactions to even larger scales were not attempted due to weight limitations of the speed mixer in our laboratory; however, this shows promise for scaling such reactions into the kilogram regime with the appropriate equipment. As these salification reactions are exothermic (i.e., reaction vessels became warm to the touch), thermal effects should be considered during further scale-up, particularly when working with concentrated HCl and larger batch masses under confined mixing conditions. Again, of particular note are the high yields, minimal impurities, low solvent use, and reduced time scales compared to solvent-based recrystallizations. These reactions also maintain low process mass intensities (PMIs) at larger scales (Table 3), reflecting the near-stoichiometric use of HCl and minimal liquid loading relative to conventional hydrochloride salt crystallization methods.

Table 3 Comparison of reported and idealized mechanochemical conditions with literature routes for hydrochloride salt formation

Material	Mechanochemical conditions reported herein						Idealized mechanochemical conditions^a		Conditions reported in literature via solution methods
	Mass of free base^b	Chloride source	Volume of liquid^c	Mass produced^d	PMI	Time (min)	Stoichiometric liquid required^c	PMI	Chloride source	PMI	Time (days)	Ref. #
a Idealized mechanochemical conditions assume stoichiometric HCl addition enabled through optimization of milling parameters to maintain complete conversion without excess acid.b Mass of free base is reported in g (above the solid black line) or mg (below the line).c Volume of liquid is reported in mL (above the solid black line) or µL (below the line), for this work the density of 12.1 M HCl(aq) is assumed to be 1.19 g mL^−1, for HCl(MeOH) density is assumed to be 0.93 g mL^−1.d Mass produced assumes 100% conversion of free base to respective HCl salt.e PMI and time calculated only for crystallization step, preparation of NicH precursor not included (reported separately using excess conc. HCl).f Estimated assuming 200 mg freebase, as substrate mass was not reported.g Most likely generated in situ from an Sb(III) chloride precursor (e.g., SbCl3, Ph3SbCl2, or Me3SbCl2).h Inferred from aqueous hydrochloride crystallization conditions (exact synthesis not reported).
NicH-Nic:H2O	100.0	12.1 M HCl(aq)	34.0	112.9	1.15	2	33.8	1.15	Conc. HCl	8.4^e	14^e	70
NicH	75.0	12.1 M HCl(aq)	50.6	97.1	1.39	2	50.7	1.39	Conc. HCl	N/A	N/A	70
NicAH	75.0	12.1 M HCl(aq)	50.6	97.2	1.39	2	50.3	1.39	12 M HCl	100^f	N/A	9
CaffH:H2O	75.0	12.1 M HCl(aq)	32.0	96.0	1.10	2	31.9	1.10	HCl(aq)	N/A	N/A	13
IsoH-Iso:H2O	101.5	12.1 M HCl(aq)	35.0	124.1	1.15	2	34.3	1.15	N/A	N/A	N/A	N/A
IsoH	100.8	12.1 M HCl(aq)	70.0	130.9	1.41	2	68.2	1.39	12 M HCl(aq)	70	“Several”	10
PicH-Pic	202.8	12.1 M HCl(aq)	70.0	233.1	1.23	10	68.2	1.22	N/A	N/A	N/A	N/A
PicH	101.2	12.1 M HCl(aq)	70.0	131.4	1.40	5	68.5	1.39	N/A	N/A	N/A	N/A
IsoAH	101.4	12.1 M HCl(aq)	70.0	131.4	1.41	5	68.1	1.39	∼0.6 M HCl(aq)	54^f	N/A	14
PicAH-PicA	101.6	12.1 M HCl(aq)	35.0	116.6	1.23	10	34.1	1.22	N/A	N/A	N/A	N/A
PicAH:H2O	203.3	12.1 M HCl(aq)	140.0	293.3	1.26	10	136.5	1.25	Unknown^g	N/A	N/A	15
PicAH	102.4	3.0 M HCl(MeOH)	550.0	132.7	4.63	15	277.3	2.71	HCl(aq)^h	N/A	1	11
CaffH	101.7	3.0 M HCl(MeOH)	175.0	120.8	2.19	5	174.6	2.19	Acetyl chloride/HCl(g)	30 (acetyl)	4	7
AcetH-Acet	103.3	3.0 M HCl(MeOH)	230.0	115.8	2.74	5	113.9	1.81	Acetyl chloride	11	7	7
AcetH:H2O	200.3	12.1 M HCl(aq)	220.0	272.5	1.70	5	109.5	1.21	Conc. HCl	7.3	30 min	120
AcetH-Acet:H2O	202.5	12.1 M HCl(aq)	110.0	239.0	1.40	5	55.4	1.12	N/A	N/A	N/A	N/A

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3.6 Structural characterization of organic HCl salts

3.6.1 Single-crystal X-ray diffraction. Slow evaporations were attempted for all novel materials in hopes of obtaining crystals suitable for analysis by SCXRD; however, only recrystallizations of PicH:H₂O were successful. PicH:H₂O crystallizes in the monoclinic space group P2₁/n featuring a single chloride ion site (Fig. 2). This crystal structure is available from the Cambridge Structural Database under deposition number 2341820.

Fig. 2 ORTEP diagram of PicH:H₂O along the crystallographic a-axis.

3.6.2 Thermal analysis. TGA was used to characterize the novel hemihydrochloride salts IsoH-Iso:H₂O, PicH-Pic, PicAH-PicA, and AcetH-Acet:H₂O, with the goal of determining their hydration state. First, since the molar mass of IsoH-Iso:H₂O is 298.73 g mol⁻¹, ca. 6% of its mass is attributed to water. This is confirmed by a ca. 7% mass reduction over a temperature range from 35 to 145 °C (thermal degradation occurs at ca. 155 °C, Fig. S22). The additional ca. 1% loss may arise from moisture content in the sample. Second, the TGA results for PicH-Pic and PicAH-PicA are inconclusive due to the inherent thermal instability of their components. PicAH thermally degrades at temperatures as low as 55.2 °C, and Pic has an even lower melting point than PicA (i.e., 110 °C vs. 136 °C), making both materials poor candidates for thermal analysis.¹³⁶ Consistent with this, thermal degradation for PicH-Pic and PicAH-PicA begins near 80 °C (Fig. S23 and S24). Prior to this, there is a small mass reduction of ca. 5%, which could arise from either the partial release of waters of hydration, resulting in a smaller than expected weight loss for a monohydrate, or the presence of “surface” water molecules (i.e., physisorbed, chemisorbed, and/or interstitial water molecules that are not part of the crystalline lattice). However, as described in Section 3.4, these materials can be synthesized under anhydrous conditions, making the presence of waters of hydration unlikely. Finally, AcetH-Acet:H₂O, with a molecular mass of 356.806 g mol⁻¹ and anticipated mass reductions of 15.3% and 19.3% for mono- and di-hydrate forms, respectively, has an experimental reduction of ca. 17% over a temperature range from 65 °C to 175 °C, before decomposing at ca. 210 °C (Fig. S25). As such, AcetH-Acet:H₂O is likely a monohydrate and the remainder of the mass loss (∼2.7%) is due to the volatilization of surface water molecules. It is also possible that AcetH-Acet:H₂O contains a non-stoichiometric amount of water, such as 1.5 water molecules per asymmetric unit, which would result in a 17.4% mass loss.⁵³

3.6.3 ^35/37Cl SSNMR. ³⁵Cl SSNMR spectra were acquired for all HCl salts under static conditions at 18.8 T, as well as under MAS conditions at 18.8 T for most samples. In order to accurately determine the EFG and CS tensor parameters, ³⁵Cl SSNMR spectra are usually acquired at two different fields. However, since chlorine has a second NMR-active isotope, ³⁷Cl (I = 3/2), ³⁷Cl SSNMR spectra were acquired for most HCl salts under static conditions at 18.8 T to enable a similar analysis.^48,49,65 MAS experiments, which can average the contributions from CSA, but only partially average those from the SOQI, enable the acquisition of spectra that allow for the facile determination of C_Q, η_Q, and δ_iso. In turn, this facilitates simulations of corresponding static NMR spectra (the latter require eight parameters to fit, including the CS tensors and Euler angles that describe the relative orientation of the EFG and CS tensors;¹³⁷ see Table 4 for definitions).

Table 4 ³⁵Cl EFG and chemical shift tensor parameters obtained from experimental measurements and DFT calculations on DFT-D2* geometry-optimized structures

Material		CQ(^35Cl)^a (MHz)	ηQ^a	δiso^b (ppm)	Ω^b (ppm)	κ^b	α^c (°)	β^c (°)	γ^c (°)
a The principal components of the EFG tensors are defined such that |V33| ≥ |V22| ≥ |V11|. The quadrupolar coupling constant and asymmetry parameter are given by CQ = eQV33/h, and hQ = (V11 − V22)/V33, respectively. The sign of CQ cannot be determined from the experimental ^35Cl spectra. Q(^35Cl)/Q(^37Cl) = −8.165/−6.435 = 1.27.b The principal components of the chemical shift tensors are defined using the frequency-ordered convention, with d11 ≥ d22 ≥ d33. The isotropic chemical shift, span, and skew are given by diso = (d11 + d22 + d33)/3, W = d11 − d33, and k = 3(d22 − diso)/W, respectively.c The Euler angles, α, β, and γ, define the relative orientation of the EFG and chemical shift tensors using the ZY′Z′′ convention for rotation. The experimental angles derived from ssNake (which uses the ZX′Z′′ convention) are adjusted to match the calculated values extracted by EFGShield, which follows the ZY′Z′′ convention.d This parameter is not reported since it has little effect on the appearance of simulated powder patterns.e Novel organic HCl salt, not previously reported.f Novel organic HCl salt, crystal structure reported herein.
NicH-Nic:H2O	Exp	3.03(2)	0.83(2)	75.6(4)	70(10)	−0.8(2)	60(15)	85(10)	9(10)
	DFT	3.52	0.92	52	17	0.07	28	12	62
NicH	Exp	5.69(4)	0.12(2)	79.9(4)	75(10)	0.1(1)	40(10)	30(5)	120(10)
	DFT	−4.72	0.42	127.1	73	−0.02	230	39	165
IsoH-Iso:H2O^e	Exp	6.33(5)	0.81(4)	74(7)	40(15)	0.5(4)	n/a^d	15(15)	n/a^d
IsoH	Exp	3.87(5)	0.83(2)	41.5(5)	57(10)	0.5(4)	40(10)	50(10)	125(15)
	DFT	3.72	0.58	65.4	81	−0.29	63	70	111
PicH-Pic^e	Exp	1.24(3)	0.78(2)	63.1(5)	30(5)	−0.7(2)	65(20)	90(10)	90(10)
PicH:H2O^f	Exp	4.20(3)	0.74(2)	28.8(4)	160(20)	0.6(1)	0(10)	50(5)	20(10)
	DFT	4.29	0.99	49.7	121	−0.26	149	79	194
PicH^e	Exp	2.25(2)	0.04(3)	25.5(4)	48(10)	−0.06(5)	90(10)	70(15)	90(30)
NicAH	Exp	7.26(3)	0.71(2)	60(7)	40(20)	0.5(4)	n/a^d	n/a^d	n/a^d
	DFT	−6.21	0.58	60.7	130	−0.42	270	90	63
IsoAH (site 1)	Exp	5.98(5)	0.74(3)	76(6)	81(20)	0.65(0.35)	90(30)	45(5)	45(20)
	DFT	5.40	0.73	75.2	87	0.01	98	43	311
IsoAH (site 2)	Exp	5.88(4)	0.57(3)	55(5)	65(15)	0.2(2)	45(20)	0(25)	124(25)
	DFT	5.83	0.54	43.2	57	0.30	104	76	212
PicAH-PicA^e	Exp	4.94(3)	0.68(2)	35.1(4)	70(5)	−0.5(3)	0(15)	52(5)	27(10)
PicAH:H2O	Exp	4.80(5)	0.81(3)	21.7(3)	110(10)	0.05(5)	0(10)	10(10)	90(10)
	DFT	5.24	0.85	57	137	−0.30	144	82	196
PicAH	Exp	9.52(6)	0.18(2)	28(10)	118(20)	−0.7(3)	n/a^d	90(15)	90(15)
	DFT	−8.66	0.00	82.3	204	−0.45	180	90	276
CaffH:H2O	Exp	5.22(4)	0.08(2)	11.1(4)	115(20)	−0.6	20(20)	67(10)	46(10)
	DFT	6.07	0.15	22.1	73	−0.55	288	85	186
CaffH	Exp	6.55(5)	0.40(2)	120(5)	10(10)	0(1)	n/a^d	n/a^d	n/a^d
	DFT	−4.61	0.57	90.7	60	−0.62	359	22	94
AcetH-Acet	Exp	3.46(3)	0.13(2)	76.5(4)	40(10)	−0.5(3)	90(20)	90(20)	0(20)
	DFT	4.95	0.31	85.7	59	−0.46	302	83	355
AcetH:H2O	Exp	3.37(3)	0.54(3)	56.2(4)	65(5)	−0.40(10)	100(10)	35(10)	90(20)
	DFT	4.08	0.60	60.6	59	−0.22	291	90	23
AcetH-Acet:H2O^e	Exp	1.59(2)	0.14(1)	58.9(4)	25(5)	0.5(2)	90(20)	25(5)	80(10)

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^35/37Cl SSNMR spectra for each form feature CT patterns that are different from one another, demonstrating the utility of ^35/37Cl SSNMR (cf. Fig. 3–5) for spectral fingerprinting. The magnitudes of C_Q reflect the degree of spherical symmetry of the ground state electron density about the Cl⁻ ion (increased magnitudes indicate less spherical symmetry), while the η_Q values describe the axial asymmetry of the EFG tensor (0 ≤ η_Q ≤ 1, where η_Q = 0 is axial). All of this, combined with the relatively short acquisition times for these spectra, makes ^35/37Cl SSNMR an ideal technique for not only obtaining spectral fingerprints, but also for studying the relationships between the ^35/37Cl EFG tensors and hydrogen bonding environments of the chloride ions (Section 3.7).

Fig. 3 Select ^35/37Cl SSNMR spectra (blue) acquired at 18.8 T and corresponding simulations (black) of the CT powder patterns. ^†It is not possible to acquire an acceptable MAS pattern of this material using a 3.2 mm rotor at 18.8 T. ^‡AcetH-Acet:H₂O is the only salt in this subset without a known structure.

Fig. 4 (A) ³⁵Cl and (B) ³⁷Cl static SSNMR spectra of IsoAH acquired at 18.8 T, along with simulated patterns (black) and two-site deconvolutions (site 1: red and site 2: green).

Fig. 5 ³⁵Cl static and MAS spectra (blue) and simulations (black, green, and red) of all synthesized HCl salts acquired at 18.8 T.

Select sets of ^35/37Cl SSNMR spectra acquired at 18.8 T are shown in Fig. 3. The appearances of the CT patterns are dominated by the SOQI, having breadths ranging from 10 to 150 kHz. All spectra of the known HCl salts feature a single CT pattern corresponding to single distinct chloride site, with the exception of those of IsoAH (Fig. 4), which feature two overlapping powder patterns, in agreement with its crystal structure.¹³⁸ The spectra show no evidence of unwanted side products (i.e., other organic HCl salts or sharp peaks indicating hydrated chloride ions), indicating that the reaction conditions for salt formation are selective for specific products.

We now consider the ³⁵Cl SSNMR spectra from the perspectives of phase identification and structural interpretation, first discussing the HCl salts of Nic, Iso, NicA, and IsoA (Fig. 5A). NicH and NicH-Nic:H₂O have distinct ³⁵Cl CT powder patterns, with the former arising from a moderate C_Q and low η_Q, and the latter from a small C_Q and high η_Q. IsoH and IsoH-Iso:H₂O are also readily differentiable, as the C_Q for IsoH is much smaller, and both EFG tensors are non-axially symmetric. The ³⁵Cl CT patterns of NicAH and IsoAH are different from those of NicH and IsoH, with a large C_Q and non-axial η_Q for NicAH, and two individual patterns of with moderate C_Q's and variable η_Q's for IsoAH (vide supra). Second, the HCl salts of Pic and PicA have very different ³⁵Cl CT patterns from simple salts, hydrates, and hemichlorides (Fig. 5B), with the exception of those of PicAH-PicA and PicAH:H₂O, which have powder patterns yielding similar quadrupolar parameters but different values of δ_iso. Finally, ³⁵Cl CT patterns for CaffH and CaffH:H₂O, as well as AcetH:H₂O, AcetH-Acet, and AcetH-Acet:H₂O, all have unique shapes and distinct sets of quadrupolar and chemical shift parameters (Fig. 5C). From this dataset, and a broader review of the data that follows, there are no clear trends in C_Q and η_Q that can be directly related to the general form of the solid (e.g., simple salts do not necessarily have chloride ions with smaller C_Q values or low η_Q values in comparison to their corresponding hydrated forms); rather, differences arise due to the nature of the local Cl⁻ hydrogen bonding environments (vide infra).

3.7 ³⁵Cl EFG tensors and molecular-level structure

Here, we compare the ³⁵Cl EFG tensors derived from quantum chemical computations with those obtained experimentally and consider their relationships with the local structural environment of the chloride ions. Dispersion-corrected plane-wave DFT geometry optimizations^101,102,139 were conducted on structural models based on their respective crystal structures; subsequently, ³⁵Cl EFG tensors were calculated (Table 4). A comparison of experimental and computed EFG tensors (Fig. S26) shows a reasonable correlation, with an RMS EFG distance (Γ_EFG) of 0.66 MHz (see SI S1 for discussion of Γ_EFG).^62,102 However, significant outliers are observed for AcetH-Acet, CaffH, and CaffH:H₂O, possibly due to dynamics that partially average their quadrupolar interactions that are not reflected in the DFT calculations, which are conducted on static structural models. To further investigate this, ³⁵Cl spectra of CaffH:H₂O and AcetH-Acet were acquired at 245 K (Fig. S27). In both cases, there is an increase in the magnitudes of both C_Q and η_Q at the lower temperature, bringing experimental and calculated values into better agreement. Removing these outliers from the original correlation plot results in better agreement, with a Γ_EFG = 0.51 MHz (Fig. 6).

Fig. 6 Relationships between principal components of the ³⁵Cl EFG tensors that have been measured experimentally and calculated from DFT-D2* geometry optimized structures. The blue line represents the linear regression fit, while the grey line represents perfect correlation. CaffH, CaffH:H₂O and AcetH-Acet are excluded (see text for details).

The ³⁵Cl EFG tensors of chloride ions depend on the surrounding H⋯Cl⁻ bonds, including their number, their lengths [r(H⋯Cl⁻)], the types of moieties involved in bonding, and their spatial arrangement. Some information on H⋯Cl⁻ bonds can be garnered directly from the quadrupolar parameters; however, DFT calculations are useful for closely examining these relationships. We note that typical H⋯Cl⁻ bonds are classified as having r(H⋯Cl⁻) ≤ 2.6 Å;¹⁴⁰ however, it is the short H⋯Cl⁻ contacts, i.e., r(H⋯Cl⁻) ≲ 2.2 Å, which largely dictate the properties of the ³⁵Cl EFG tensors.^58,61

Summarizing, the ³⁵Cl EFG tensor orientations, magnitudes and signs of C_Q, and structural relationships are consistent with those from previous reports on a wide range of organic HCl salts (Table 5). For systems with one short H⋯Cl⁻ or two short H⋯Cl⁻ contacts with ∠(H⋯Cl⋯H) ≥ 140°, the magnitudes of C_Q are moderate to large, their signs are negative (i.e., positive V₃₃ components), and V₃₃ is oriented along or near the direction of the shortest contact. In cases with two short contacts, small to moderate magnitudes of C_Q are observed, their signs are positive, with V₃₃ oriented approximately perpendicular to the H⋯Cl⁻⋯H planes. Values of r(H⋯Cl⁻) are generally found to be shorter for short contacts involving RCOOH moieties than those associated with 1° and 2° amides. The situation becomes more complex for two or three short contacts and additional hydrogen bonds – this is where DFT calculations have great value. Below, we discuss the ³⁵Cl EFG tensors and their orientation (Fig. 7 and 8) and the impact of different H⋯Cl⁻ contacts, including r(H⋯Cl⁻) and the identities of the hydrogen-bonding moieties (Table 5).

Table 5 List of H⋯Cl⁻ contacts, associated moieties, and calculated ³⁵Cl SSNMR parameters for HCl salts, as determined from X-ray diffraction derived crystal structures

Material	Number of short contacts	r(H⋯Cl^−) of shortest contact (Å)^a	r(H⋯Cl^−) of 2nd shortest contact (Å)^a	r(H⋯Cl^−) of 3rd shortest contact (Å)^a	r(H⋯Cl^−) of 4th shortest contact (Å)^a	Orientation of V33	CQ^b (MHz)	ηQ^b
a H⋯Cl^− hydrogen bonds (r(H⋯Cl^−) ≤ 2.6 Å), as determined via energy minimization and geometry optimization with DFT plane wave calculations. Short H⋯Cl^− contacts are those with r(H⋯Cl^−) ≲ 2.2 Å.b CQ values and signs listed here are obtained from DFT calculations; the latter are unobtainable from ^35/37Cl SSNMR experiments. It is noted that since Q(^35Cl) = −8.165 fm^2, positive and negative values of CQ correspond to negative and positive EFGs, respectively. Definitions of CQ and ηQ are given in Table 4.c Anomalous ^35Cl EFG tensor orientation, see discussion in text.
NicH	1	2.063 RR′NH	2.217 RNH2	—	—	Along/near the shortest H⋯Cl^− contact	−4.72	0.42
NicH-Nic:H2O	0	2.206 H2O	2.249 H2O	2.290 RNH2	—	Perpendicular to a plane of three hydrogen atoms	3.52	0.92
NicAH	1	1.962 RCOOH	—	—	—	Along/near the shortest H⋯Cl^− contact	−6.21	0.58
IsoH	2	2.164 RR′NH	2.197 RNH2	—	—	Approx. perpendicular to H⋯Cl^−⋯H plane	3.72	0.58
IsoAH (site 1)	2	1.979 RCOOH	2.183 RR′NH	—	—	Approx. perpendicular to H⋯Cl^−⋯H plane	5.40	0.73
IsoAH (site 2)	2	1.987 RCOOH	2.120 RR′NH	—	—	Approx. perpendicular to H⋯Cl^−⋯H plane	5.83	0.54
PicH:H2O	2	2.170 H2O	2.220 H2O	2.250 RR′NH	—	Approx. perpendicular to H⋯Cl^−⋯H plane	4.29	0.99
PicAH:H2O	2	2.157 H2O	2.180 H2O	2.236 RR′NH	—	Approx. perpendicular to H⋯Cl^−⋯H plane	5.24	0.85
PicAH	2	2.036 RCOOH	2.212 RR′NH	—	—	Along/near the shortest H⋯Cl^− contact	−8.66	0.00
AcetH:H2O	3	2.120 ROH	2.183 H2O	2.208 H2O	2.313 RR′NH	Approx. perpendicular to H⋯Cl^−⋯H plane	4.08	0.60
AcetH-Acet	2	2.067 ROH	2.251 RR′NH	2.285 RR′NH	—	Approx. perpendicular to H⋯Cl^−⋯H planes	4.95	0.31
CaffH:H2O	2	2.192 H2O	2.195 H2O	2.272 H2O	2.337 H2O	Along/near the shortest H⋯Cl^− contact^c	6.07	0.15
CaffH	1	1.970 RR′NH	—	—	—	Perpendicular to the hydrogen bond^c	−4.61	0.57

---

Fig. 7 ³⁵Cl EFG tensor orientations in: (A) NicH, NicH-Nic:H₂O, and NicAH; (B) IsoH and both chloride ions in IsoAH; and (C) PicH:H₂O, PicAH:H₂O, and PicAH. Red dotted lines indicate short contacts.

Fig. 8 ³⁵Cl EFG tensor orientations in: (A) AcetH:H₂O, and AcetH-Acet; and (B) CaffH:H₂O, and CaffH. Red dotted lines indicate short contacts.

We begin by comparing NicAH, NicH, and NicH-Nic:H₂O (Fig. 7A). NicAH and NicH each have a single short contact, which results in moderate values of C_Q (−6.21 MHz and −4.72 MHz, respectively), with V₃₃, aligning near the axis of the short contact. The magnitude of C_Q is larger for NicAH due to the RCOOH moiety, which generally has shorter r(H⋯Cl⁻) values than amide groups, and hence, larger magnitudes of C_Q. NicH-Nic:H₂O is distinct, with three H⋯Cl⁻ bonds in a pyramidal arrangement, leading to a C_Q with a relatively small magnitude (3.52 MHz) and sign opposite to those above, with V₃₃ oriented roughly perpendicular to a plane formed by the three hydrogen bonds.

IsoH and IsoAH (Fig. 7B) have one and two chloride ion sites, respectively. The chloride ion environments all feature two short contacts arranged in “V” formations. The C_Q values are all positive, with larger magnitudes in IsoAH because of the RCOOH moieties, which result in shorter values of r(H⋯Cl⁻). In all cases, V₃₃ is oriented approximately perpendicular to the H⋯Cl⁻⋯H plane.

We next compare PicH:H₂O, PicAH:H₂O, PicAH, and PicH. For the hydrates PicH:H₂O and PicAH:H₂O, the C_Q values are positive, with V₃₃ oriented perpendicular to the H⋯Cl⁻⋯H planes featuring an RR′NH moiety and H₂O molecule (Fig. 7C). PicAH has a large C_Q = −8.66 MHz and η_Q = 0.0, which results from two short H⋯Cl⁻ contacts with hydrogen atoms positioned on opposite sides of the chloride ion,^58,122 and V₃₃ aligned closely to the shorter H⋯Cl⁻ contact. This stands in contrast with PicH (for which the crystal structure is unknown), which has a small experimentally-determined C_Q = 2.25 MHz, suggesting the presence of longer hydrogen bonds with surrounding 1° and 2° amides.

AcetH:H₂O and AcetH-Acet both have low-to-moderate C_Q values. AcetH-Acet has three short H⋯Cl⁻ contacts and a low η_Q value (Fig. 8A). The C_Q magnitude is due to the comparatively larger number of contacts, whereas the latter results from the pyramidal arrangement of hydrogen bonds that approaches C₃ symmetry. AcetH:H₂O has two short contacts and two additional hydrogen bonds with H₂O molecules. In both cases, C_Q is positive and the alignment of V₃₃ is roughly perpendicular to the short contacts.

Finally, CaffH and CaffH:H₂O have distinct chloride ion environments (Fig. 8B). CaffH has a single short contact (RR′NH), and as expected, a negative, moderate C_Q. However, V₃₃ is oriented perpendicular to this bond rather than along it, which is unusual. CaffH:H₂O has four hydrogen bonds, two of which are short contacts, all arising from water molecules, which is a coordination motif rarely observed in organic HCl salts. V₃₃ is oriented near the shortest hydrogen bond. The uncommon hydrogen bonding networks in CaffH and CaffH:H₂O may account for the anomalous ³⁵Cl EFG tensor orientations and contribute to the discrepancies between calculated and experimental NMR parameters; for CaffH:H₂O, this may also be the result of dynamical motions of the water molecules that influence the experimentally measured ³⁵Cl EFGs.

4. Conclusions

This study demonstrated the (i) rapid and quantitative mechanochemical syntheses of sixteen HCl salts, including anhydrous forms, hydrates, and hemihydrochlorides (five of which are novel), as well as the formation of PicH:H₂O via slow evaporation; (ii) advantages of mechanochemical salification, including negligible waste, minimal solvent use, quantitative yields, accelerated discovery of solid forms, and scalability; (iii) complexities inherent to solid-state chemistry, where common assumptions and behaviors derived from solution chemistry do not apply (e.g., a myriad of factors can influence kinetic vs. thermodynamic products and the limitations of using pK_a's to make predictions regarding protonation of pyridyl nitrogens); (iv) value of ^35/37Cl SSNMR spectroscopy for fingerprinting of chloride salts, impurity detection, and structural elucidation; and (v) the application of plane-wave DFT calculations of ³⁵Cl EFG tensors to investigate their relationships to the hydrogen bonding environments of chloride ions.

The combination of mechanochemical salification and characterization via ^35/37Cl SSNMR offers substantial benefits at both laboratory and industrial scales. On the laboratory side of things, screening for solid forms is significantly accelerated, making the discovery and identification of rare solid forms, such as hemihydrochlorides, more straightforward. At an industrial scale, mechanochemistry has great potential for increased efficiency and reduced costs, which benefits the manufacturer and consumer, due to reduction in solvent, energy use, safety hazards, waste disposal, and unwanted by-products. The usefulness of ^35/37Cl SSNMR in laboratory settings is clear from this work and many preceding accounts; however, it could play an important role in industrial settings for spectral fingerprinting and impurity detection, especially since MAS experiments are not absolutely required (this eliminates the costs of rotors, tedious sample packing, and opens the possibility of looking at complex dosage formulations like pills and capsules directly) – and, only a single magnetic field is necessary.^57,141 Furthermore, it could aid in the quantification of HCl salts, examination of disproportion,¹⁴¹ and streamlining of early-stage screening and selection, all of which are essential for time-sensitive discovery and in formulation pipelines, where rapid decisions on salt forms are needed prior to scaling up or advancing through regulatory pathways.

While the current work focuses specifically on organic HCl salts, this mechanochemical salification method is broadly applicable to a wider range of APIs. The same principles could be extended to form salts with polyprotic acids (e.g., H₂SO₄, H₃PO₄, etc.) or other pharmaceutically relevant counterions (e.g., HBr, HNO_3, methanesulfonic acid, etc.), potentially enabling the rapid generation of diverse salt forms beyond those traditionally accessed via solution-based methods. This versatility highlights the utility of mechanochemistry for the development of many new solid forms across a vast landscape of APIs.

Conflicts of interest

The authors have no conflict of interest to declare.

Data availability

CCDC 2341820 (picolinamide HCl monohydrate) contains the supplementary crystallographic data for this paper.¹⁴²

Supplementary information (SI) is available. See DOI: https://doi.org/10.1039/d5mr00156k.

Acknowledgements

The authors thank the Florida State University and the National High Magnetic Field Laboratory for funding this research. The National High Magnetic Field Laboratory is supported by the National Science Foundation through NSF/DMR-2128556, NSF/DMR-1644779, and the State of Florida. The authors thank Jason Kitchen and Peter Gor'kov for configuring probes for ³⁷Cl NMR experimentation, and the staff at the National High Magnetic Field Laboratory for their continued support. A portion of this research used resources provided by the X-ray Crystallography Center and the Materials Characterization Laboratory at the FSU Department of Chemistry and Biochemistry. V. K. R. is grateful to the NSF Research Experiences for Undergraduates (REU) program for supporting a term of summer research at the FSU and the NHMFL.

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Footnote

† Deceased February 2026.

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