Whitepaper
Salts
en
Published May 12, 2026
Solid form change is one of the most underestimated sources of solubility loss in drug development. Three mechanisms account for most of the risk: polymorph conversion to a less soluble stable form, salt disproportionation reverting an ionized species back to the free base or free acid, and amorphous recrystallization as a dispersion loses its amorphous character over time. Each operates at a different stage of development and demands a different study design. Treating them as a single risk leads to programs that run the wrong studies at the wrong time.
When a development team reports the solubility of a drug candidate, they are reporting the solubility of a specific physical form under specific conditions. Change the form, and the solubility changes with it. A metastable polymorph can be two to ten times more soluble than the thermodynamically stable polymorph of the same compound. A salt can be orders of magnitude more soluble than its corresponding free base. An amorphous form can dissolve to apparent concentrations far exceeding the crystalline phase equilibrium solubility. These differences are what makes solid form selection central to early development strategy.
The risk that receives less attention is the reverse: the form that was selected and characterized can change during the development process, and when it does, the solubility changes with it. This is not a single risk with a single mechanism. It operates at two distinct levels, each requiring a different response.
At the drug substance level, polymorphism and hydrate or solvate formation can cause a less soluble form to emerge during manufacturing, storage, or crystallization scale-up. These changes are driven primarily by the thermodynamic landscape of the molecule itself, though formulation processes can provide the conditions that trigger them — wet granulation, for example, introduces water that can drive hydrate formation in APIs with accessible hydrated phases, directly reducing aqueous solubility. At the formulation level, specific solubility enhancement strategies carry inherent stability risks: a salt can revert to the free form through disproportionation, and an amorphous dispersion can recrystallize over time. These are not failures of the strategy. They are the stability obligations that come with choosing it.
This article examines three of the most development-critical solid form changes: polymorph conversion, salt disproportionation, and amorphous recrystallization. Each belongs to a different risk category and requires a different evaluation approach.
Most small molecule drugs can crystallize in more than one crystalline lattice arrangement. These polymorphs are chemically identical but physically distinct, and the differences in packing energy translate directly to differences in solubility and dissolution rate. The thermodynamically stable form at a given temperature and humidity is almost always the least soluble. Metastable forms, which are kinetically accessible but thermodynamically disfavored, dissolve more readily but will convert toward the stable form given sufficient time, moisture, or mechanical energy.
Polymorph conversion is primarily a drug substance level event. While manufacturing conditions can provide the opportunity, the underlying driver is the thermodynamic landscape of the molecule itself: mechanical stress during milling, solvent exposure during wet granulation, thermal cycling during drying, or extended storage at elevated humidity can each create the conditions under which a metastable form converts to a more stable, less soluble one. The formulation choice may change the risk factor.
Comprehensive polymorph screening is a de-risking activity that drug substance scientists and formulation scientists both have a stake in. The earlier it is done, the more it protects downstream decisions. A team that completes polymorph screening after the manufacturing process has been designed has less room for troubleshooting.
Abbott Laboratories launched Norvir in 1996 as a semisolid capsule formulation. The drug substance was characterized as a single crystalline form. Two years into the commercial lifecycle, batches began failing dissolution specifications. Investigation revealed that a second polymorph, Form II, had appeared and was seeding itself throughout production. Form II was significantly less soluble than Form I, and the formulation that had been optimized around Form I no longer delivered the intended dissolution profile. ¹² The product was withdrawn and reformulated at an estimated cost exceeding $250 million.
The detail that matters most for development programs is not the magnitude of the failure. It is that Form II was not inherently undetectable. It required specific crystallization conditions that were not part of the original screening set. A more extensive polymorph screen using diverse solvents, temperatures, and humidity conditions, combined with competitive slurry maturation experiments, would have had a reasonable probability of surfacing it at preformulation. The information was available. The decision to generate it was not made.
Salt formation is the most widely used approach to increasing the equilibrium solubility of ionizable drugs. By converting the free acid or free base to a salt, the team selects a form that can be orders of magnitude more soluble than the parent compound, while retaining the handling and processing advantages of a crystalline solid. This is a well-founded strategy with a long regulatory and development history.
The stability question that needs to be answered before a salt is chosen is whether the ionized form will remain ionized under the conditions the product will encounter. Every salt of a weak base/acid has a characteristic pH, called pHmax, at which the solubility of the salt equals the solubility of the free base. Below pHmax, the salt is thermodynamically more stable and more soluble. Above pHmax, the free form is favored, and the driving force for disproportionation exists. The width of the stability window is determined primarily by the pKa of the drug relative to the pKa of the counterion. A strong acid counterion paired with a weak base drug produces a large ΔpKa and a wide stability window. A weak acid counterion narrows that window considerably.
pH-solubility profiling across the physiologically and process-relevant pH range maps where that crossover occurs for each salt candidate. Slurry competition experiments at pH values representative of typical manufacturing and GI conditions confirm whether the salt reverts to the free form under those conditions. These are preformulation tools. Identifying a counterion with an unfavorable pHmax after the formulation has been designed forces a late stage change that is far more disruptive than the screening work required to avoid it. ³
Excipients that shift the local microenvironmental pH are a secondary factor. Magnesium stearate and croscarmellose sodium have both been documented in association with disproportionation of weak base salts, and their influence matters in the context of formulation design. But an excipient can only accelerate a conversion that is thermodynamically possible. If the salt is inherently prone to disproportionation at typical formulation pH conditions, changing the excipient set manages the rate. It does not eliminate the risk. The risk is managed by choosing the right counterion at the start.
Sertraline is a weak base marketed as its hydrochloride salt. It has been studied extensively as a model compound for salt disproportionation precisely because multiple salt forms are accessible and their disproportionation behaviors span a meaningful range.
Hsieh and colleagues demonstrated, across a series of sertraline salt forms, that disproportionation tendency is directly related to pHmax. Salt forms with lower pHmax values — meaning the free base becomes thermodynamically favored at a lower pH — showed higher extents of disproportionation under equivalent conditions. The buffering capacity of the salt, which governs how readily the system can resist local pH shifts, also contributed independently of pHmax.³ The practical implication of this work is that pHmax is a calculable and measurable quantity that is available at the salt selection stage, before any formulation decisions are made. It provides a rational basis for ranking candidate salts by disproportionation risk, and it explains why two salts of the same compound with similar aqueous solubility can perform very differently under formulation stress.
For development programs, the sertraline data illustrates a broader principle: the information needed to anticipate disproportionation risk does not require a formulated product. It requires a pH-solubility profile and an understanding of the pKa landscape of each candidate salt. Running this analysis during counterion screening, rather than after a salt has been selected and a formulation has been designed, preserves the team's options at the stage when the cost of acting on the finding is lowest.
Amorphous solid dispersions generate their solubility advantage by removing the crystal lattice energy barrier entirely. The drug is dispersed in a polymer matrix without long-range crystalline order, and the resulting amorphous form dissolves to apparent concentrations that can be 10 to 50-fold higher than the crystalline equilibrium. This is the most powerful solubility lever available for poorly soluble drugs with adequate permeability.
The thermodynamic reality of amorphous forms is that they are metastable. An amorphous drug generally exists at higher free energy than its crystalline counterpart, and given sufficient molecular mobility, it can convert toward the crystalline form over time. The polymer matrix is the primary barrier against this conversion, and its effectiveness determines how long the dispersion retains its solubility advantage. In that sense, polymer selection and physical stability management are not peripheral considerations in ASD development. They are central to it.
The recrystallization risk is governed primarily by the relationship between the glass transition temperature (Tg) of the dispersion and the conditions the product encounters. At temperatures well below the Tg, molecular mobility is low and recrystallization is slow. As conditions approach the Tg, either through elevated temperature or through moisture-induced plasticization, mobility increases and the window for nucleation opens.⁶ What development teams frequently underestimate is how much the Tg can shift during manufacturing: a dispersion with a nominal Tg of 80 °C can drop to 50 °C or lower when the polymer absorbs moisture during film coating or during exposure to high-humidity environments in packaging operations.⁸ The manufacturing excursion is transient. The nucleation event it enables is not.
Detection is a separate challenge. Routine XRPD has a practical detection limit of roughly 1 to 5 percent crystalline content by weight.⁷ A dispersion can lose amorphous content progressively and remain analytically clean by XRPD while dissolution performance is already declining. Treating solid-state characterization data as the primary stability endpoint, without paired dissolution testing at each stability time point, creates the conditions for a product that passes specification until it suddenly does not.
The three solid form changes described above are governed by different mechanisms and require different evaluation approaches. Treating them as a single risk category leads to programs that do the wrong studies at the wrong stage.
For polymorphism: characterize the full solid form landscape before formulation begins. Use at least 20 to 30 diverse crystallization conditions covering different solvent classes, temperatures, humidity, and seeding. Run competitive slurry maturation experiments to identify the thermodynamically stable form. Simulate process conditions including milling and wet granulation to confirm that the selected form does not convert under manufacturing stress. This work belongs at preformulation, before the salt selection, before the manufacturing process is designed.
For salt disproportionation: evaluate pHmax and buffering capacity during counterion screening. Use pH-solubility profiling to identify the pH at which each candidate salt transitions to the free form. Run slurry competition experiments at pH values representative of GI and manufacturing conditions. Rank candidate salts by pHmax and ΔpKa before committing to a counterion. A salt with a pHmax below the pH of typical excipient microenvironments carries an inherent disproportionation risk that formulation adjustments can only partially mitigate. Once a salt is selected, Raman spectroscopy and HPLC-based free base quantification can confirm the risk remains manageable under intended manufacturing conditions.
For ASD recrystallization: challenge the Tg, not just the shelf. Measure the Tg of the dispersion at the intended drug loading and at least one loading above it. Run physical stability studies at conditions that bracket the Tg, including humidity-plasticized conditions that simulate manufacturing excursions. At every stability time point, assess dissolution performance alongside solid-state characterization. A dispersion that retains amorphous character by XRPD but shows declining dissolution is already failing. The Tg data and the dissolution data together determine whether the polymer system is adequate, not either one alone.
The table below summarises each risk by stage, trigger, key studies, and critical timing.
Risk | Stage | Primary Trigger | Key Evaluation Studies | Critical Timing |
Polymorph conversion | Drug substance | Mechanical stress, solvent exposure, humidity, thermal cycling | Polymorph screen (≥20–30 conditions, diverse solvent classes); competitive slurry maturation; process simulation (milling, wet granulation) | Preformulation — before salt selection and manufacturing process design |
Salt disproportionation | Formulation / drug substance | pHmax of salt form; local pH shift from excipients + moisture | pH-solubility profiling; pHmax / ΔpKa ranking of candidate salts; slurry competition at GI and manufacturing pH; Raman / free base HPLC under process conditions | During counterion screening — before salt is selected |
Amorphous recrystallization | Formulation / manufacturing | Moisture-induced Tg depression, thermal excursion during processing | Tg measurement at intended and higher drug loadings; humidity-plasticized physical stability; paired dissolution + XRPD at every stability timepoint | During formulation design; manufacturing risk assessment before scale-up |
Solid form instability occurs when the physical form of a drug substance or formulation changes under manufacturing or storage conditions. The three most development-critical mechanisms are polymorph conversion (a metastable crystalline form converts to a more stable, less soluble form), salt disproportionation (a salt reverts to the free base or acid through a microenvironmental pH shift), and amorphous recrystallization (an amorphous dispersion nucleates and partially crystallizes, losing its solubility advantage). Each is triggered differently and requires a distinct evaluation strategy.
Polymorph screening should be completed at preformulation — before salt selection and before the manufacturing process is designed. A comprehensive screen covers at least 20–30 crystallization conditions across diverse solvent classes, temperatures, and humidity levels, combined with competitive slurry maturation experiments to identify the thermodynamically stable form. Screening conducted after formulation development is underway limits the team's ability to act on what it finds.
The key tool is pH-solubility profiling to determine the pHmax of each candidate salt — the pH at which the salt and free base have equal solubility. Salt forms with a pHmax below the pH of typical excipient microenvironments carry an inherent disproportionation risk. Ranking candidate salts by pHmax and ΔpKa during counterion screening, supported by slurry competition experiments at representative GI and manufacturing pH values, provides a rational basis for selection before any formulation decisions are made.
Routine XRPD has a practical detection limit of approximately 1 to 5 percent crystalline content by weight. A dispersion can lose meaningful amorphous content and show declining dissolution performance while remaining analytically clean by XRPD. Dissolution testing must be run alongside solid-state characterization at every stability timepoint — the two datasets together determine whether the polymer system is adequate.
Underestimating how much the glass transition temperature (Tg) can drop during manufacturing. A dispersion with a nominal Tg of 80 °C can fall to 50 °C or lower when the polymer absorbs moisture during film coating or high-humidity packaging operations. Physical stability studies that do not include humidity-plasticized conditions will not capture this risk. The manufacturing excursion is transient; the nucleation event it enables is not.
Crystal Pharmatech provides solid-state characterization services at both the drug substance and formulation level. For drug substance risks, our polymorph screening programs are designed to map the full solid form landscape before formulation decisions are made, not after. For formulation stability risks, we assess salt disproportionation under real processing and excipient conditions and evaluate ASD physical stability at conditions that reflect actual manufacturing and storage exposure. We help development teams understand where solubility can decrease, and what it takes to prevent it.
Related: See Crystal Pharmatech's Polymorph Screening, Salt and Co-crystal Screening, and Solid-State Characterization services.
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