How We Solved the Crystallisation Issue of a Pharmaceutical Raw Material During Storage: Practical Procedure and Prevention

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Crystallization of pharmaceutical raw materials, particularly active pharmaceutical ingredients (APIs), is a common issue in operations where long-term stability is required. This phenomenon occurs due to changes in temperature, humidity, or unsuitable excipient composition, which can lead to undesirable changes in solubility, efficacy, or even product degradation. In one of our cases, a customer faced repeated crystallization of a sensitive API during storage, jeopardizing the entire production batch. The solution involved a combination of analytical methods, adjustments to storage conditions, and the targeted use of stabilizing additives. This article describes the specific steps we took to identify and permanently resolve the problem.

Problem identification: When crystallization threatens raw material quality

Crystallization of pharmaceutical raw materials during storage is a frequent but serious problem that can lead to degradation of active substances, loss of mixture homogeneity, or even failure to meet pharmacopoeial requirements. In our case, it involved an organic compound with low water solubility, which began spontaneously forming microscopic crystals at temperatures below 15 °C. These crystals were not merely an aesthetic defect—their presence impaired the dispersibility of the raw material in subsequent production steps and increased the risk of clogging filtration systems.

The problem only became apparent after several months of storage, when the customer reported unusual behavior of the raw material during processing. Sample analysis revealed that crystallization was accelerated by a combination of low temperature and the presence of trace impurities, which acted as nucleation centers. A key finding was that the raw material could not simply be refiltered—while the crystals redissolved upon heating, the process was irreversible in terms of the original particle morphology.

Analytical Methods and Causes: How We Identified the Root of the Problem

To systematically address the issue, we first had to precisely characterize the conditions under which crystallization occurs. We employed a combination of thermal analysis (DSC) and polarized light microscopy to monitor the temperature range of phase transitions and the morphology of the forming crystals. DSC analysis showed that the raw material lacked a stable amorphous phase—even mild supercooling led to exothermic energy release, signaling spontaneous crystallization.

We further investigated the influence of moisture and impurities using chromatographic methods (HPLC) and mass spectrometry. We found that even trace amounts (< 0.1%) of certain solvents or synthesis by-products significantly reduce the crystallization temperature. These impurities entered the raw material during the supplier’s manufacturing process and were not sufficiently removed during final purification. Based on these findings, we defined critical parameters for storage as well as specifications for future deliveries.

Photo: National Cancer Institute / Unsplash

Technical Solution: Optimizing Storage Conditions and Raw Material Adjustment

The first step was an immediate solution for the existing raw material stock. We implemented controlled heating to 25–30 °C for 48 hours, followed by slow cooling to 18 °C, which enabled recrystallization into a more stable form. This process was monitored using in-line spectroscopy (NIR) to ensure uniform temperature distribution and prevent local overheating. After recrystallization, the raw material was subjected to grinding to a defined particle size (D90 < 50 μm), which improved its dispersibility.

For a long-term solution, we adjusted the storage conditions: the temperature was maintained within the range of 18–22 °C with relative humidity below 40%. Furthermore, we collaborated with the supplier to modify the production process to minimize impurities that promote crystallization. As a preventive measure, we introduced regular sample testing using DSC before each delivery, providing a tool for early detection of potential issues.

Prevention and Recommendations: How to Avoid Similar Issues in the Future

The experience from this case demonstrated the importance of a comprehensive understanding of raw material behavior throughout the entire chain, from production to storage. For manufacturers and distributors of pharmaceutical raw materials, we recommend implementing the following measures: 1) Detailed characterization of phase transitions during raw material development, including stability testing at various temperatures and humidity levels. 2) Regular monitoring of storage conditions using dataloggers for real-time temperature and humidity tracking. 3) Collaboration with suppliers to optimize purification processes to eliminate impurities that promote crystallization.

An important step is also training personnel to recognize the first signs of crystallization – for example, changes in powder fluidity or the formation of agglomerates. For sensitive raw materials, the use of stabilizers such as amorphizing agents, which prevent crystallization, can be considered. Although these solutions may increase costs, they pay off in the long run by reducing the risk of defects and complaints. Prevention is always more effective than solving problems afterward.

Photo: National Cancer Institute / Unsplash

The Role of Packaging Materials in the Stability of Pharmaceutical Raw Materials

Crystallization of sensitive pharmaceutical raw materials is often linked to unsuitable packaging that does not provide sufficient protection against moisture, temperature fluctuations, or mechanical stress. In our case, we found that the original low-barrier polyethylene packaging allowed moisture penetration, which initiated crystal formation. The problem was particularly evident with hygroscopic substances, where even small amounts of absorbed water led to local supersaturation of the solution and subsequent nucleation.

The solution was to switch to multilayer packaging with aluminum foil or metallized PET, which ensures near-zero water vapor permeability. It is also important to consider the mechanical properties of the packaging – for example, with powdered raw materials, static electricity or friction during transport can trigger crystal seed formation. In practice, the use of antistatic additives in the packaging material and minimizing free space in the package to limit particle movement have proven effective. For liquid raw materials, the chemical compatibility of the packaging with the contents is key to prevent migration of substances from the plastic into the product.

Dynamic Monitoring of Storage Conditions: Technologies for Early Risk Detection

The traditional approach based on regular manual checks of storage conditions often fails to detect short-term fluctuations that can trigger crystallization. In our project, we implemented a system for continuous monitoring of temperature, humidity, and vibrations using wireless sensors with cloud data storage. These sensors enabled the detection of, for example, a nighttime temperature drop below the critical threshold of 15 °C, which was not apparent from daily records but was sufficient to initiate crystallization in a sensitive raw material.

A key advantage of dynamic monitoring is the ability to set warning thresholds and automatic notifications. For example, if the relative humidity in the storage area exceeds 40%, the system immediately alerts the responsible personnel, enabling preventive action—such as activating dehumidifiers or relocating stock to more stable conditions. The monitoring data was also used to create temperature maps of the warehouse, which revealed problematic zones with insufficient air circulation. For long-term storage, we recommended investing in climate-controlled storage containers with temperature regulation within a range of ±2 °C.

Collaboration with Raw Material Suppliers: How to Prevent Issues at the Purchasing Stage

Many crystallization issues can be prevented at the supplier selection and raw material specification stage. In our case, we found that the key factors were not only the purity of the substance but also its crystalline form and particle size distribution. Suppliers often deliver raw materials in different polymorphic forms, which vary in stability and sensitivity to storage conditions. Therefore, we began requiring suppliers to provide detailed information on crystalline structure and recommended storage conditions in the technical specification.

An important step was also the implementation of incoming raw material inspections using thermal analysis (DSC) and X-ray diffraction (XRD), which allow for quick verification of the polymorphic form and detection of any impurities that promote crystallization. We established close collaboration with suppliers to optimize the production process—for example, by adjusting crystallization parameters during raw material manufacturing to ensure the most stable final form. In some cases, we also agreed on deliveries in smaller batches with a shorter storage period, which reduced the risk of degradation during long-term storage.

Do You Need to Ensure Stability of Pharmaceutical Raw Materials?

Every pharmaceutical raw material requires an individual approach to ensure stability and safety. GCG Group provides detailed technical and safety data sheets (SDS) for all supplied raw materials and advises on the selection of suitable additives or storage conditions for your specific application. Contact us – or browse our catalogue of over 1,300 products.