There is a current and growing need for the development of efficient early-stage drug discovery methods, as well as the continuous manufacturing of drug delivery vessels and precise dosing of high-potency drugs.
A team of Researchers from the United States have created a solvent-free organic vapor jet printing method which can precisely, and continuously, print medicines for accelerated drug screening protocols with a high dosage accuracy.
A significant portion of drug research currently centers around high potency medicines, personalized medicines and alternative drug delivery vehicles. Traditional approaches to these research areas have been proven to be imprecise or inflexible in their versatility for customized medicine formulations.
A lot of problems are associated with trying to balance drug discovery rate, dose customizability and manufacturing scalability, which often results in a compromise of at least one of the factors. Aside from compromise, drug formulations are prone to a wide range of potential issues, even for the simplest of drugs. Within this, the drug discovery and manufacturing processes can encounter problems associated with low solubility, low dissolution rates, micronization, nanonization and bioavailability.
The team of Researchers from the US have now created a new printing method for the production of solvent-free drugs. The printing process utilized deposited nanostructured films of small molecular pharmaceutical ingredients onto various substrates.
The Researchers printed caffeine, paracetamol, ibuprofen, tamoxifen, BAY 11-7082 and fluorescein molecules onto the surface of glass, Tegaderm, Listerine tabs and stainless-steel microneedle substrates on the scale of µg/cm2.
The Researchers employed an organic vapor jet printing (OVJP) method to perform the printing itself and was performed in a glove box under a nitrogen atmosphere.
The Researchers also utilized a wide range of characterization methods to identify the printed molecules, including X-ray diffraction (XRD, Newport 6-circle kappa), optical microscopy (Zeiss), scanning electron microscopy (SEM, FEI Nova 200 Nanolab), thermogravimetric analysis (TGA, TA Instruments Thermogravimetric Analyzer Q500), Ultraviolet-visible spectroscopy (UV-Vis, Ocean Optics USB + 2000), ultra-performance liquid chromatography (UPLC, Waters Acquity H Class with a C18 column), dissolution rate measurements and solubility tests. The team also used theoretical modeling approaches based on Noyes–Whitney and Levich theories.
The printing process converted pharmaceutical ingredient molecules into high-surface area films with a nanocrystalline morphology, without the need for a solvent. The printed films were found to possess similar crystallographic order and chemistry and the initial powder precursor molecules. In addition, the team found that the process was controlled and the dissolution rate exhibited order-of-magnitude enhancements.
The printed drug films also exhibited an affinity for the killing of cancer cells in an efficient manner. The Researchers tested this ability in-vitro for breast and ovarian cancer cell cultures suspended in an aqueous media. In these tests, it was the by tamoxifen and BAY 11-7082 films which showed promise and a similar behaviour as drugs pre-dissolved in dimethyl sulfoxide solvents. However, these drugs could perform without the need to pre-dissolve them in organic solvents.
In previous research, amorphous dispersions have been used to increase the solubility of active pharmaceutical ingredients (APIs), but have often suffered from stability issues. In this new approach, the nano- and micro-crystalline nature of the printed drug films means that the stability of the active ingredients does not suffer when the dissolution rates are increased and enables one of the biggest drug discovery compromises to become nulled.
In a general sense, the ability to print pure molecular drugs without the need for a solvent opens up an alternative approach to drug screening and continuous manufacturing processes. Such processes will now be able to produce an accurate dosage, chemical and structural stability and processing flexibility, without affecting the functionality of the drug.
The printing process will provide many benefits for early stage drug discovery methods, by limiting the need for solvents for poorly soluble drugs, providing alternative developments in drug delivery vehicles (such as films for transdermal drug delivery, directly coated patches, microneedles, encapsulated dissolvable films or implants) and will provide an efficient manufacture and administration of high potency APIs (HPAPIs) with individually tailored dosing and nanogram level accuracy.
The printing process may also find itself in commercial continuous manufacturing plants, as the process negates the need for mixing and powder preparation and ultimately leads to a simple process which can be scaled-up.
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“Printing of small molecular medicines from the vapor phase”- Shalev O., et al, Nature Communications, 2017, DOI: 10.1038/s41467-017-00763-6