To Crush or Not to Crush: Novel Drug Formulations

To Crush or Not to Crush: Novel Drug Formulations
Bridget Williams, PharmD, Allina Health 

Background: Ambulatory care providers often adjust dosage forms and administration of oral medications for patients who may have trouble swallowing or have malabsorptive issues to overcome. Tablets can be cut or crushed, while capsules can be opened and sprinkled on food or into a liquid for the ease of administration to patients. Along with the medication package insert, the Institute for Safe Medicine Practices (ISMP) “Do Not Crush” list is often used by healthcare providers to determine if a medication can be safely split or crushed. However, this list was last updated in 2016, and there is no set schedule in place for regular revisions. In recent years, two notable novel drug formulations have been developed to improve oral bioavailability: nanocrystals and amorphous solid dispersions. There are now over 30 FDA-approved oral medications that utilize one of these two innovative technologies. The availability of these new formulations has led to a lack of clarity over which products may be altered prior to administration. A recent review by Uttaro, et al. aims to summarize evidence to guide healthcare practitioners in the proper administration of these drug formulations.

Evidence & Discussion: Both nanocrystal and amorphous solid dispersion formulations were developed to increase the oral bioavailability of tablets and capsules by increasing drug dissolution rate in the gastrointestinal (GI) tract. Nanocrystal technology involves reducing active drug into tiny crystalline particles and packaging these particles into a unit dose. The smaller particle size increases the total surface area of drug and thus enhances dissolution rate and rate of absorption. However, publications by Jermain, et al. and Zhang, et al. highlight the unique stability of drug nanocrystals positioned within the polymers of a tablet. Cutting or crushing the nanocrystal formulation disrupts the stabilizing polymer structure and allows moisture to initiate crystal growth. As the nanocrystals begin to clump together and form larger crystals outside of the integrity of the original tablet, surface area decreases and drug dissolution actually slows compared to the intended effect of this technology. Examples of drugs that are supplied in a nanocrystal formulation include: Emend™ (aprepitant), TriCor™ (fenofibrate), and Triglide™ (fenofibrate).

Amorphous solid dispersions are created by converting the crystalline form of a drug into an amorphous form, usually by the processes of spray drying or continuous hot melt extrusion. Amorphous drug particles are packaged into a unit dose without any particular order, which differs from the typical order of drug particles in a crystal lattice. Polymers stabilize the amorphous solid drug into position so that a tablet can be manufactured, but the non-ordered formulation allows for the amorphous particles to easily dissociate when exposed to moisture in the GI tract. This allows for stability of the dosage form until administration, when the drug dissolution rate occurs more quickly than it would in a crystal lattice preparation. However, the types of polymer must be carefully chosen to stabilize amorphous solid dispersions without allowing the drug to convert back into its crystalline form. It is hypothesized that cutting or crushing an amorphous solid dispersion tablet disrupts the precise polymer stabilization and leads to conversion of the drug back to crystalline form, destroying the intended properties of quick dissolution and enhanced bioavailability. In a study by Pas, et al., oral amorphous solid dispersions of Sporanox (itraconazole), Intelence (etravirine), Noxafil DR (posaconazole), and Norvir (ritonavir) were assessed in vitro for their dissolution rates when fully intact versus after crushing each with a mortar and pestle. Interestingly, crushed ritonavir, itraconazole, and posaconazole showed a more rapid dissolution rate compared to the intact amorphous solid dispersions, which the authors suggest may be due to destruction of tablet film coatings. Crushed etravirine showed a significantly slower dissolution rate compared to intact etravirine tablets. The authors recognize that the study was limited in generalizing its findings to true drug-release kinetics and bioavailability in the human body.

Clinical Impact: Healthcare providers should recognize which oral medications utilize nanocrystal or amorphous solid dispersion technology in order to advocate for appropriate administration of these products. Cutting, crushing, or dissolving nanocrystal or amorphous solid dispersions may inadvertently lead to disruption of the intended drug release properties and could lead to reduced therapeutic efficacy or amplified adverse effects. It is challenging to predict the change in drug dissolution, bioavailability, and effect after cutting or crushing these novel formulations. Until additional in vivo research can characterize the impact of manipulating nanocrystal and amorphous solid dispersion formulations, these medications should be administered intact per manufacturer guidance. Pharmacists may recommend an alternative dosage form for patients who are unable to swallow whole tablets or capsules. Furthermore, an update to the ISMP “Do Not Crush” list is warranted to include novel drug formulations that may contribute to undesirable clinical outcomes if cut or crushed.



  1. Institute for Safe Medicine Practices. Oral dosage forms that should not be crushed. 2016. Accessed from:

  2. Uttaro E, Pudipeddi M, Schweighardt, A, Zhao F. To crush or not to crush: A brief review of novel tablets and capsules prepared from nanocrystal amorphous solid dispersion technologies. Am J Health-Syst Pharm. 2021; 78: 389-394. doi: 10.1093/ajhp/zxaa412.

  3. Jermain SV, Brough C, Williams RO. Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery - An update. Int J Pharm. 2018; 535: 379-392. doi: 10.1016/j.ijpharm.2017.10.051.

  4. Zhang X, Xing H, Zhao Y, Ma Z. Pharmaceutical dispersion techniques for dissolution and bioavailability enhancement of poorly water-soluble drugs. Pharmaceutics. 2018; 10(74): 1-33. doi: 10.3390/pharmaceutics10030074.

  5. Pas T, Verbert S, Appeltans B, Van den Mooter G. The influence of crushing amorphous solid dispersion dosage forms on the in vitro dissolution kinetics. Int J Pharm. 2020; 573: 118884. doi: 10.1016/j.ijpharm.2019.118884.